Anti-inflammatory medicaments

ABSTRACT

Novel compounds and methods of using those compounds for the treatment of inflammatory conditions are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein comprises the step of contacting the kinase protein with the novel compounds.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/886,329, filed Jul. 6, 2004, which is a continuation-in-part of U.S.patent application Ser. No. 10/746,460, filed Dec. 24, 2003, whichclaims the benefit of provisional application Ser. No. 60/437,487, filedDec. 31, 2002, Ser. No. 60/437,403, filed Dec. 31, 2002, Ser. No.60/437,415 filed Dec. 31, 2002, Ser. No. 60/437,304, filed Dec. 31,2002, and Ser. No. 60/463,804, filed Apr. 18, 2003. Each of theseapplications is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds and methods of usingthose compounds to treat anti-inflammatory diseases.

2. Description of the Prior Art

Basic research has recently provided the life sciences community with anunprecedented volume of information on the human genetic code and theproteins that are produced by it. In 2001, the complete sequence of thehuman genome was reported (Lander, E. S. et al. Initial sequencing andanalysis of the human genome. Nature (2001) 409:860; Venter, J. C. etal. The sequence of the human genome. Science (2001) 291:1304).Increasingly, the global research community is now classifying the50,000+ proteins that are encoded by this genetic sequence, and moreimportantly, it is attempting to identify those proteins that arecausative of major, under-treated human diseases.

Despite the wealth of information that the human genome and its proteinsare providing, particularly in the area of conformational control ofprotein function, the methodology and strategy by which thepharmaceutical industry sets about to develop small moleculetherapeutics has not significantly advanced beyond using native proteinactive sites for binding to small molecule therapeutic agents. Thesenative active sites are normally used by proteins to perform essentialcellular functions by binding to and processing natural substrates ortranducing signals from natural ligands. Because these native pocketsare used broadly by many other proteins within protein families, drugswhich interact with them are often plagued by lack of selectivity and,as a consequence, insufficient therapeutic windows to achieve maximumefficacy. Side effects and toxicities are revealed in such smallmolecules, either during preclinical discovery, clinical trials, orlater in the marketplace. Side effects and toxicities continue to be amajor reason for the high attrition rate seen within the drugdevelopment process. For the kinase protein family of proteins,interactions at these native active sites have been recently reviewed:see J. Dumas, Protein Kinase Inhibitors: Emerging Pharmacophores1997-2001, Expert Opinion on Therapeutic Patents (2001) 11: 405-429; J.Dumas, Editor, New challenges in Protein Kinase Inhibition, in CurrentTopics in Medicinal Chemistry (2002) 2: issue 9.

It is known that proteins are flexible, and this flexibility has beenreported and utilized with the discovery of the small molecules whichbind to alternative, flexible active sites with proteins. For review ofthis topic, see Teague, Nature Reviews/Drug Discovery, Vol. 2, pp.527-541 (2003). See also, Wu et al., Structure, Vol. 11, pp. 399-410(2003). However these reports focus on small molecules which bind onlyto proteins at the protein natural active sites. Peng et al., Bio.Organic and Medicinal Chemistry Ltrs., Vol. 13, pp. 3693-3699 (2003),and Schindler, et al., Science, Vol. 289, p. 1938 (2000) describeinhibitors of ab1 kinase. These inhibitors are identified in WOPublication No. 2002/034727. This class of inhibitors binds to the ATPactive site while also binding in a mode that induces movement of thekinase catalytic loop. Pargellis et al., Nature Structural Biology, Vol.9, p. 268 (2002) reported inhibitors p38 alpha-kinase also disclosed inWO Publication No. 00/43384 and Regan et al., J. Medicinal Chemistry,Vol. 45, pp. 2994-3008 (2002). This class of inhibitors also interactswith the kinase at the ATP active site involving a concomitant movementof the kinase activation loop.

More recently, it has been disclosed that kinases utilize activationloops and kinase domain regulatory pockets to control their state ofcatalytic activity. This has been recently reviewed (see, e.g., M. Huseand J. Kuriyan, Cell (2002) 109:275).

SUMMARY OF THE INVENTION

The present invention is broadly concerned with new compounds for use intreating anti-inflammatory conditions and methods of treating suchconditions. In more detail, the inventive compounds have the formula

wherein:

-   -   R¹ is selected from the group consisting of aryls (preferably        C₆-C₁₈, and more preferably C₆-C₁₂) and heteroaryls;    -   each X and Y is individually selected from the group consisting        of —O—, —S—, —NR₆—, —NR₆SO₂—, —NR₆CO—, alkynyls (preferably        C₁-C₁₈, and more preferably C₁-C₁₂), alkenyls (preferably        C₁-C₁₈, and more preferably C₁-C₁₂), alkylenes (preferably        C₁-C₁₈, and more preferably C₁-C₁₂), —O(CH₂)_(h)—, and        —NR₆(CH₂)_(h)—, where each h is individually selected from the        group consisting of 1, 2, 3, or 4, and where for each of        alkylenes (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        —O(CH₂)_(h)—, and —NR₆(CH₂)_(h)—, one of the methylene groups        present therein may be optionally double-bonded to a side-chain        oxo group except that where —O(CH₂)_(h)— the introduction of the        side-chain oxo group does not form an ester moiety;    -   A is selected from the group consisting of aromatic (preferably        C₆-C₁₈, and more preferably C₆-C₁₂), monocycloheterocyclic, and        bicycloheterocyclic rings;    -   D is phenyl or a five- or six-membered heterocyclic ring        selected from the group consisting of pyrazolyl, pyrrolyl,        imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl,        thiadiazolyl, thienyl, pyridyl, and pyrimidyl;    -   E is selected from the group consisting of phenyl, pyridinyl,        and pyrimidinyl;    -   L is selected from the group consisting of —C(O)— and —S(O)₂—;    -   j is 0 or 1;    -   m is 0 or 1;    -   n is 0 or 1;    -   p is 0 or 1;    -   q is 0 or 1;    -   t is 0 or 1;    -   Q is selected from the group consisting of

-   -   each R₄ group is individually selected from the group consisting        of —H, alkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        aminoalkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        alkoxyalkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        aryls (preferably C₆-C₁₈, and more preferably C₆-C₁₂), aralkyls        (preferably C₆-C₁₈, and more preferably C₆-C₁₂ and preferably        C₁-C₁₈, and more preferably C₁-C₁₂), heterocyclyls, and        heterocyclylalkyls except when the R₄ substituent places a        heteroatom on an alpha-carbon directly attached to a ring        nitrogen on Q;    -   when two R₄ groups are bonded with the same atom, the two R₄        groups optionally form an alicyclic or heterocyclic 4-7 membered        ring;    -   each R₅ is individually selected from the group consisting of        —H, alkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        aryls (preferably C₆-C₁₈, and more preferably C₆-C₁₂),        heterocyclyls, alkylaminos (preferably C₁-C₁₈, and more        preferably C₁-C₁₂), arylaminos (preferably C₆-C₁₈, and more        preferably C₆-C₁₂), cycloalkylaminos (preferably C₁-C₁₈, and        more preferably C₁-C₁₂), heterocyclylaminos, hydroxys, alkoxys        (preferably C₁-C₁₈, and more preferably C₁-C₁₂), aryloxys        (preferably C₆-C₁₈, and more preferably C₆-C₁₂), alkylthios        (preferably C₁-C₁₈, and more preferably C₁-C₁₂), arylthios        (preferably C₆-C₁₈, and more preferably C₆-C₁₂), cyanos,        halogens, perfluoroalkyls (preferably C₁-C₁₈, and more        preferably C₁-C₁₂), alkylcarbonyls (preferably C₁-C₁₈, and more        preferably C₁-C₁₂), and nitros;    -   each R₆ is individually selected from the group consisting of        —H, alkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        allyls, and β-trimethylsilylethyl;    -   each R₇ is individually selected from the group consisting of        alkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂), phenyl,        naphthyl, aralkyls (wherein the aryl is preferably C₆-C₁₈, and        more preferably C₆-C₁₂, and wherein alkyl is preferably C₁-C₁₈,        and more preferably C₁-C₁₂), heterocyclyls, and        heterocyclylalkyls (wherein the alkyl is preferably C₁-C₁₈, and        more preferably C₁-C₁₂);    -   each R₉ group is individually selected from the group consisting        of —H, —F, and alkyls (preferably C₁-C₁₈, and more preferably        C₁-C₁₂), wherein when two R₉ groups are geminal alkyl groups,        said geminal alkyl groups may be cyclized to form a 3-6 membered        ring;    -   G is alkylene (preferably C₁-C₈, and more preferably C₁-C₄),        N(R₆), O;    -   each Z is individually selected from the group consisting of —O—        and —N(R₄)—; and    -   each ring of formula (IA) optionally includes one or more of R₇,        where R₇ is a noninterfering substituent individually selected        from the group consisting of —H, alkyls (preferably C₁-C₁₈, and        more preferably C₁-C₁₂), aryls (preferably C₆-C₁₈, and more        preferably C₆-C₁₂), heterocyclyls, alkylaminos (preferably        C₁-C₁₈, and more preferably C₁-C₁₂), arylaminos (preferably        C₆-C₈, and more preferably C₆-C₁₂), cycloalkylaminos (preferably        C₁-C₁₈, and more preferably C₁-C₁₂), heterocyclylaminos,        hydroxys, alkoxys (preferably C₁-C₁₈, and more preferably        C₁-C₁₂), aryloxys (preferably C₆-C₁₈, and more preferably        C₆-C₁₂), alkylthios (preferably C₁-C₁₈, and more preferably        C₁-C₁₂), arthylthios, cyanos, halogens, nitrilos, nitros,        alkylsulfinyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        alkylsulfonyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        aminosulfonyls, and perfluoroalkyls (preferably C₁-C₁₈, and more        preferably C₁-C₁₂).

In one preferred embodiment, the compound has the structure of formula(I) except that:

-   -   when Q is Q-3 or Q-4, then the compound of formula (I) is not

-   -   when Q is Q-7, q is 0, and R₅ and D are phenyl, then A is not        phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl;    -   when Q is Q-7, R₅ is —OH, Y is —O—, —S—, or —CO—, m is 0, n is        0, p is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not        thienyl, thiazolyl, or phenyl;    -   when Q is Q-7, R₅ is —OH, m is 0, n is 0, p is 0, t is 0, and A        is phenyl, pyridyl, or thiazolyl, then D is not thienyl,        thiazolyl, or phenyl;    -   when Q is Q-7, then the compound of formula (I) is not

-   -   when Q is Q-8, then Y is not —CH₂O—;    -   when Q is Q-8, the compound of formula (I) is not

-   -   when Q is Q-9, then the compound of formula (I) is not

-   -   when Q is Q-10, t is 0, and E is phenyl, then any R₇ on E is not        an o-alkoxy;    -   when Q is Q-10, then the compound of formula (I) is not

-   -   when Q is Q-11, t is 0, and E is phenyl, then any R₇ on E is not        an o-alkoxy;    -   when Q is Q-11, then the compound of formula (I) is not

-   -   when Q is Q-15, then the compound of formula (I) is not

-   -   when Q is Q-16 and Y is —NH—, then

-   -    of formula (I) is not biphenyl;    -   when Q is Q-16 and Y is —S—, then

-   -    of formula (I) is not phenylsulfonylaminophenyl or        phenylcarbonylaminophenyl;    -   when Q is Q-16 and Y is —SO₂NH—, then the compound of        formula (I) is not

-   -   when        -   Q is        -   Q-16        -   and        -   Y is —CONH—, then

-   -    of formula (I) is not imidazophenyl;    -   when Q is Q-16 and Y is —CONH—, then the compound of formula (I)        is not

-   -   when Q is Q-16 and t is 0, then

-   -    of formula (I) is not phenylcarbonylphenyl, pyrimidophenyl,        phenylpyrimidyl, pyrimidyl, or N-pyrolyl;    -   when Q is Q-17, then the compound of formula (I) is not

-   -   when Q is Q-21, then the compound of formula (I) is not

-   -   when Q is Q-22, then the compound of formula (I) is selected        from the group consisting of

-   -   when Q is Q-22 and q is 0, then the compound of formula (I) is        selected from the group consisting of

-   -   when Q is Q-23, then the compound of formula (I) is not

-   -   when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of        formula (I) is selected from the group consisting of

-   -   -   wherein each W is individually selected from the group            consisting of —CH— and —N—;        -   each G₁ is individually selected from the group consisting            of —O—, —S—, and —N(R₄)—; and        -   * denotes the point of attachment to Q-24, Q-25, Q-26, or            Q-31 as follows:

-   -   -   -   wherein each Z is individually selected from the group                consisting of —O— and —N(R₄)—;

    -   when Q is Q-31, then the compound of formula (I) is not

-   -   when Q is Q-28 or Q-29 and t is 0, then the compound of        formula (I) is not

-   -   when Q is Q-28 or Q-29 and Y is an ether linkage, then the        compound of formula (I) is not

-   -   when Q is Q-28 or Q-29 and Y is —CONH—, then the compound of        formula (I) is not

-   -   when Q is Q-32, then

-   -    is not biphenyl, benzoxazolylphenyl, pyridylphenyl or        bipyridyl;    -   when Q is Q-32, Y is —CONH—, q is 0, m is 0, and

-   -    of formula (I) is —CONH—, then A is not phenyl;    -   when Q is Q-32, q is 0, m is 0, and

-   -    is —CONH—, then the compound of formula (I) is not

-   -   when Q is Q-32, D is thiazolyl, q is 0, t is 0, p is 0, n is 0,        and m is 0, then A is not phenyl or 2-pyridone;    -   when Q is Q-32, D is oxazolyl or isoxazolyl, q is 0, t is 0, p        is 0, n is 0, and m is 0, then A is not phenyl;    -   when Q is Q-32, D is pyrimidyl q is 0, t is 0, p is 0, n is 0,        and m is 0, then A is not phenyl;    -   when Q is Q-32 and Y is an ether linkage, then

-   -    of formula (I) is not biphenyl or phenyloxazolyl;    -   when Q is Q-32 and Y is —CH═CH—, then

-   -    of formula (I) is not phenylaminophenyl;    -   when Q is Q-32, then the compound of formula (I) is not

-   -   when Q is Q-35 as shown

-   -    wherein G is selected from the group consisting of —O—, —S—,        —NR₄—, and —CH₂—, k is 0 or 1, and u is 1, 2, 3, or 4, then

-   -    is selected from the group consisting of

-   -   except that the compound of formula (I) is not

Even more preferably, R₁ as discussed above is selected from the groupconsisting of 6-5 fused heteroaryls, 6-5 fused heterocyclyls, 5-6 fusedheteroaryls, and 5-6 fused heterocyclyls, and even more preferably, R₁is selected from the group consisting of

-   -   each R₂ is individually selected from the group consisting of        —H, alkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        aminos, alkylaminos (preferably C₁-C₁₈, and more preferably        C₁-C₁₂), arylaminos (preferably C₆-C₁₈, and more preferably        C₆-C₁₂), cycloalkylaminos (preferably C₁-C₁₈, and more        preferably C₁-C₁₂), heterocyclylaminos, halogens, alkoxys        (preferably C₁-C₈, and more preferably C₁-C₂), and hydroxys; and    -   each R₃ is individually selected from the group consisting of        —H, alkyls (preferably C₁-C₁₈, and more preferably C₁-C₂),        alkylaminos (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        arylaminos (preferably C₆-C₁₈, and more preferably C₆-C₁₂),        cycloalkylaminos (preferably C₁-C₁₈, and more preferably        C₁-C₁₂), heterocyclylaminos, alkoxys (preferably C₁-C₁₈, and        more preferably C₁-C₁₂), hydroxys, cyanos, halogens,        perfluoroalkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        alkylsulfinyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        alkylsulfonyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        R₄NHSO₂—, and —NHSO₂R₄.

Finally, in another preferred embodiment, wherein A is selected from thegroup consisting of aromatic, monocycloheterocyclic, andbicycloheterocyclic rings; and most preferably phenyl, naphthyl,pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl,oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl,indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl,benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl,imidazopyrimidinyl, purinyl, and

-   -   where each W₁ is individually selected from the group consisting        of —CH— and —N—.

An additional class of compounds useful in the invention have theformula

A-T-(L)_(n)-(NH)_(p)-D(E)_(q)-(Y)_(t)-Q  (IB)

wherein:

-   -   Y is selected from the group consisting of —O—, —S—, —NR₆—,        —NR₆SO₂—, —NR₆CO—, alkynyls (preferably C₁-C₁₈, and more        preferably C₁-C₁₂), alkenyls (preferably C₁-C₁₈, and more        preferably C₁-C₁₂), alkylenes (preferably C₁-C₁₈, and more        preferably C₁-C₁₂), —O(CH₂)_(h)—, and —NR₆(CH₂)_(h)—, where each        h is individually selected from the group consisting of 1, 2, 3,        or 4, and where for each of alkylenes (preferably C₁-C₁₈, and        more preferably C₁-C₁₂), —O(CH₂)_(h)—, and —NR₆(CH₂)_(h)—, one        of the methylene groups present therein may be optionally        double-bonded to a side-chain oxo group except that where        —O(CH₂)_(h)— the introduction of the side-chain oxo group does        not form an ester moiety;    -   A is selected from the group consisting of aromatic (preferably        C₆-C₁₈, and more preferably C₆-C₁₂), monocycloheterocyclic, and        bicycloheterocyclic rings; and most preferably phenyl, naphthyl,        pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl,        isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl,        thiadiazolyl, indolyl, indazolyl, benzimidazolyl,        benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl,        benzofuranyl, benzothienyl, pyrazolylpyrimidinyl,        imidazopyrimidinyl, purinyl, and

-   -    where each W1 is individually selected form the group        consisting of —CH— and —N—.    -   D is phenyl or a five- or six-membered heterocyclic ring        selected from the group consisting of pyrazolyl, pyrrolyl,        imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl,        thiadiazolyl, thienyl, pyridyl, and pyrimidyl;    -   E is selected from the group consisting of phenyl, pyridinyl,        and pyrimidinyl;    -   L is selected from the group consisting of —C(O)— and —S(O)₂—;    -   T is NR₆, O, alkylene (preferably C₁-C₁₂, more preferably        C₁-C₄), —O(CH₂)_(h)—, or —NR₆(CH₂)_(h)—, where each h is        individually selected from the group consisting of 1, 2, 3, or        4, or T is absent wherein A is directly bonded to        -(L)_(n)(NH)_(p)-D-(E)_(q)-(Y)_(t)-Q;    -   n is 0 or 1;    -   p is 0 or 1;    -   q is 0 or 1;    -   t is 0 or 1;    -   v is 1, 2, or 3;    -   x is 1 or 2;    -   Q is selected from the group consisting of formulae Q₃₆-Q₅₉,        inclusive;    -   each R₄ group is individually selected from the group consisting        of —H, alkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        aminoalkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        alkoxyalkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        aryls (preferably C₆-C₁₈, and more preferably C₆-C₁₂), aralkyls        (preferably C₆-C₁₈, and more preferably C₆-C₁₂ and preferably        C₁-C₁₈, and more preferably C₁-C₁₂), heterocyclyls, and        heterocyclylalkyls except when the R₄ substituent places a        heteroatom on an alpha-carbon directly attached to a ring        nitrogen on Q;    -   when two R₄ groups are bonded with the same atom, the two R₄        groups optionally form an alicyclic or heterocyclic 4-7 membered        ring;    -   each R₆ is individually selected from the group consisting of        —H, alkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂),        allyls, and B-trimethylsilylethyl;    -   each R₈ is individually selected from the group consisting of        alkyls (preferably C₁-C₁₈, and more preferably C₁-C₁₂), phenyl,        naphthyl, aralkyls (wherein the aryl is preferably C₆-C₁₈, and        more preferably C₆-C₁₂), wherein alkyl is preferably C₁-C₁₈, and        more preferably C₁-C₁₂), heterocyclyls, and heterocyclylalkyls        (wherein the alkyl is preferably C₁-C₁₈, and more preferably        C₁-C₁₂);    -   each R₉ group is individually selected from the group consisting        of —H, —F, and alkyls (preferably C₁-C₁₈, and more preferably        C₁-C₁₂), wherein when two R₉ groups are geminal alkyl groups,        said geminal alkyl groups may be cyclized to form a 3-6 membered        ring;    -   each R₉ group is individually selected from the group consisting        of —F, and alkyls (preferably C₁-C₁₈, and more preferably        C₁-C₁₂), wherein when two R₉ groups are geminal alkyl groups,        said geminal alkyl groups may be cyclized to form a 3-6 membered        ring;    -   each R₁₀ is alkyl or perfluoroalkyl;    -   G is alkylene (preferably C₁-C₈, and more preferably C₁-C₄),        N(R₆), O;    -   each Z is individually selected from the group consisting of —O—        and —N(R₄)—; and each ring of formula (I) optionally includes        one or more of R_(7′), where R₇ is a substituent individually        selected from the group consisting of —H, alkyls (preferably        C₁-C₁₈, and more preferably C₁-C₁₂), aryls (preferably C₆-C₁₈,        and more preferably C₆-C₁₂), heterocyclyls, alkylaminos        (preferably C₁-C₁₈, and more preferably C₁-C₁₂), arylaminos        (preferably C₆-C₁₈, and more preferably C₆-C₁₂),        cycloalkylaminos (preferably C₁-C₁₈, and more preferably        C₁-C₁₂), heterocyclylaminos, hydroxys, alkoxys (preferably        C₁-C₁₈, and more preferably C₁-C₁₂), perfluoroalkoxys        (preferably C₁-C₈, more preferably C₁-C₄), aryloxys (preferably        C₆-C₁₈, and more preferably C₆-C₁₂), alkylthios (preferably        C₁-C₁₈, and more preferably C₁-C₁₂), arthylthios, cyanos,        halogens, nitrilos, nitros, alkylsulfinyls (preferably C₁-C₁₈,        and more preferably C₁-C₁₂), alkylsulfonyls (preferably C₁-C₁₈,        and more preferably C₁-C₁₂), aminosulfonyls, perfluoroalkyls        (preferably C₁-C₁₈, and more preferably C₁-C₁₂);    -    aminooxaloylamino; alkylaminooxaloylamino;        dialkylaminooxaloylamino; morpholinooxaloylamino;        piperazinooxaloylamino; alkoxycarbonylamino;        heterocyclyloxycarbonylamino; heterocyclylalkyloxycarbonylamino;        heterocyclylcarbonylamino; heterocyclylalkylcarbonylamino;        aminoalkyloxycarbonylamino; alkylaminoalkyloxycarbonylamino; or        dialkylaminoalkyloxycarbonylamino.

In a preferred embodiment, A as described above is selected from thegroup consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl,furyl, pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl,oxadiazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl,benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl,benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and

where each W₁ is individually selected from the group consisting of —CH—and —N—.

Q groups Q-36 through Q-59 are set forth below. In an additionallypreferred embodiment, Q is taken from Q-37, Q-39, Q-41, Q-42, Q-43,Q-44, Q-47, Q-48, Q-54, and Q-57; in a more preferred embodiment, Q istaken from Q-39, Q-41, Q-42, Q-43, Q-44, Q-47, Q-48, and Q-54.

With respect to the method of using the novel compounds, the activationstate of a kinase is determined by the interaction of switch controlligands and complemental switch control pockets. One conformation of thekinase may result from the switch control ligand's interaction with aparticular switch control pocket while another conformation may resultfrom the ligand's interaction with a different switch control pocket.Generally interaction of the ligand with one pocket, such as the “on”pocket, results in the kinase assuming an active conformation whereinthe kinase is biologically active. Similarly, an inactive conformation(wherein the kinase is not biologically active) is assumed when theligand interacts with another of the switch control pockets, such as the“off” pocket. The switch control pocket can be selected from the groupconsisting of simple, composite and combined switch control pockets.Interaction between the switch control ligand and the switch controlpockets is dynamic and therefore, the ligand is not always interactingwith a switch control pocket. In some instances, the ligand is not in aswitch control pocket (such as occurs when the protein is changing froman active conformation to an inactive conformation). In other instances,such as when the ligand is interacting with the environment surroundingthe protein in order to determine with which switch control pocket tointeract, the ligand is not in a switch control pocket. Interaction ofthe ligand with particular switch control pockets is controlled in partby the charge status of the amino acid residues of the switch controlligand. When the ligand is in a neutral charge state, it interacts withone of the switch control pockets and when it is in a charged state, itinteracts with the other of the switch control pockets. For example, theswitch control ligand may have a plurality of OH groups and be in aneutral charge state. This neutral charge state results in a ligand thatis more likely to interact with one of the switch control pocketsthrough hydrogen boding between the OH groups and selected residues ofthe pocket, thereby resulting in whichever protein conformation resultsfrom that interaction. However, if the OH groups of the switch controlligand become charged through phosphorylation or some other means, thepropensity of the ligand to interact with the other of the switchcontrol pockets will increase and the ligand will interact with thisother switch control pocket through complementary covalent bindingbetween the negatively or positively charged residues of the pocket andligand. This will result in the protein assuming the oppositeconformation assumed when the ligand was in a neutral charge state andinteracting with the other switch control pocket.

Of course, the conformation of the protein determines the activationstate of the protein and can therefore play a role in protein-relateddiseases, processes, and conditions. For example, if a metabolic processrequires a biologically active protein but the protein's switch controlligand remains in the switch control pocket (i.e. the “off” pocket) thatresults in a biologically inactive protein, that metabolic processcannot occur at a normal rate. Similarly, if a disease is exacerbated bya biologically active protein and the protein's switch control ligandremains in the switch control pocket (i.e. the “on” pocket) that resultsin the biologically active protein conformation, the disease conditionwill be worsened. Accordingly, as demonstrated by the present invention,selective modulation of the switch control pocket and switch controlligand by the selective administration of a molecule will play animportant role in the treatment and control of protein-related diseases,processes, and conditions.

One aspect of the invention provides a method of modulating theactivation state of a kinase, preferably p38 α-kinase and including boththe consensus wild type sequence and disease polymorphs thereof. Theactivation state is generally selected from an upregulated ordownregulated state. The method generally comprises the step ofcontacting the kinase with a molecule having the general formula (I).When such contact occurs, the molecule will bind to a particular switchcontrol pocket and the switch control ligand will have a greaterpropensity to interact with the other of the switch control pockets(i.e., the unoccupied one) and a lesser propensity to interact with theoccupied switch control pocket. As a result, the protein will have agreater propensity to assume either an active or inactive conformation(and consequently be upregulated or downregulated), depending upon whichof the switch control pockets is occupied by the molecule. Thus,contacting the kinase with a molecule modulates that protein'sactivation state. The molecule can act as an antagonist or an agonist ofeither switch control pocket. The contact between the molecule and thekinase preferably occurs at a region of a switch control pocket of thekinase and more preferably in an interlobe oxyanion pocket of thekinase. In some instances, the contact between the molecule and thepocket also results in the alteration of the conformation of otheradjacent sites and pockets, such as an ATP active site. Such analteration can also effect regulation and modulation of the active stateof the protein. Preferably, the region of the switch control pocket ofthe kinase comprises an amino acid residue sequence operable for bindingto the Formula I molecule. Such binding can occur between the moleculeand a specific region of the switch control pocket with preferredregions including the α-C helix, the α-D helix, the catalytic loop, theactivation loop, and the C-terminal residues or C-lobe residues (allresidues located downstream (toward the C-end) from the Activationloop), the glycine rich loop, and combinations thereof. When the bindingregion is the α-C helix, one preferred binding sequence in this helix isthe sequence IIHXKRXXREXXLLXXM, (SEQ ID NO. 2). When the binding regionis the catalytic loop, one preferred binding sequence in this loop isDIIHRD (SEQ ID NO. 3). When the binding region is the activation loop,one preferred binding sequence in this loop is a sequence selected fromthe group consisting of DFGLARHTDD (SEQ ID NO.4), EMTGYVATRWYR (SEQ IDNO. 5), and combinations thereof. When the binding region is in theC-lobe residues, one preferred binding sequence is WMHY (SEQ ID NO. 6).When the binding region is in the glycine rich loop one preferredbinding sequence is YGSV (SEQ ID NO. 7). When a biologically inactiveprotein conformation is desired, molecules which interact with theswitch control pocket that normally results in a biologically activeprotein conformation (when interacting with the switch control ligand)will be selected. Similarly, when a biologically active proteinconformation is desired, molecules which interact with the switchcontrol pocket that normally results in a biologically inactive proteinconformation (when interacting with the switch control ligand) will beselected. Thus, the propensity of the protein to assume a desiredconformation will be modulated by administration of the molecule. Inpreferred forms, the molecule will be administered to an individualundergoing treatment for a condition selected from the group consistingof human inflammation, rheumatoid arthritis, rheumatoid spondylitis,ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock,endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adultrespiratory distress syndrome, stroke, reperfusion injury, neuraltrauma, neural ischemia, psoriasis, restenosis, chronic pulmonaryinflammatory disease, bone resorptive diseases, graft-versus-hostreaction, Chron's disease, ulcerative colitis, inflammatory boweldisease, pyresis, and combinations thereof. In such forms, it will bedesired to select molecules that interact with the switch control pocketthat generally leads to a biologically active protein conformation sothat the protein will have the propensity to assume the biologicallyinactive form and thereby alleviate the condition. It is contemplatedthat the molecules of the present invention will be administerable inany conventional form including oral, parenteral, inhalation, andsubcutaneous. It is preferred for the administration to be in the oralform. Preferred molecules include the preferred compounds of formula(I), as discussed above.

Another aspect of the present invention provides a method of treating aninflammatory condition of an individual comprising the step ofadministering a molecule having the general formula (I) to theindividual. Such conditions are often the result of an overproduction ofthe biologically active form of a protein, including kinases. Theadministering step generally includes the step of causing said moleculeto contact a kinase involved with the inflammatory process, preferablyp38 α-kinase. When the contact is between the molecule and a kinase, thecontact preferably occurs in an interlobe oxyanion pocket of the kinasethat includes an amino acid residue sequence operable for binding to theFormula I molecule. Preferred binding regions of the interlobe oxyanionpocket include the α-C helix region, the α-D helix region, the catalyticloop, the activation loop, the C-terminal residues, the glycine richloop residues, and combinations thereof. When the binding region is theα-C helix, one preferred binding sequence in this helix is the sequenceIIHXKRXXREXXLLXXM, (SEQ ID NO. 2). When the binding region is thecatalytic loop, one preferred binding sequence in this loop is DIIHRD(SEQ ID NO. 3). When the binding region is the activation loop, onepreferred binding sequence in this loop is a sequence selected from thegroup consisting of DFGLARHTDD (SEQ ID NO.4), EMTGYVATRWYR (SEQ ID NO.5), and combinations thereof. Such a method permits treatment of thecondition by virtue of the modulation of the activation state of akinase by contacting the kinase with a molecule that associates with theswitch control pocket that normally leads to a biologically active formof the kinase when interacting with the switch control ligand. Becausethe ligand cannot easily interact with the switch control pocketassociated with or occupied by the molecule, the ligand tends tointeract with the switch control pocket leading to the biologicallyinactive form of the protein, with the attendant result of a decrease inthe amount of biologically active protein. Preferably, the inflammatorycondition is selected from the group consisting of human inflammation,rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma,gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negativesepsis, toxic shock syndrome, adult respiratory distress syndrome,stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis,restenosis, chronic pulmonary inflammatory disease, bone resorptivediseases, graft-versus-host reaction, Chron's disease, ulcerativecolitis, inflammatory bowel disease, pyresis, and combinations thereof.As with the other methods of the invention, the molecules may beadministered in any conventional form, with any convention excipients oringredients. However, it is preferred to administer the molecule in anoral dosage form. Preferred molecules are again selected from the groupconsisting of the preferred formula (I) compounds discussed above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a naturally occurring mammalianprotein in accordance with the invention including “on” and “off” switchcontrol pockets 102 and 104, respectively, a transiently modifiableswitch control ligand 106, and an active ATP site 108;

FIG. 2 is a schematic representation of the protein of FIG. 1, whereinthe switch control ligand 106 is illustrated in a binding relationshipwith the off switch control pocket 104, thereby causing the protein toassume a first biologically downregulated conformation;

FIG. 3 is a view similar to that of FIG. 1, but illustrating the switchcontrol ligand 106 in its charged-modified condition wherein the OHgroups 110 of certain amino acid residues have been phosphorylated;

FIG. 4 is a view similar to that of FIG. 2, but depicting the proteinwherein the phosphorylated switch control ligand 106 is in a bindingrelationship with the on switch control pocket 102, thereby causing theprotein to assume a second biologically-active conformation differentthan the first conformation of FIG. 2;

FIG. 4 a is an enlarged schematic view illustrating a representativebinding between the phosphorylated residues of the switch control ligand106, and complemental residues Z+ from the on switch control pocket 102;

FIG. 5 is a view similar to that of FIG. 1, but illustrating inschematic form possible small molecule compounds 116 and 118 in abinding relationship with the off and on switch control pockets 104 and102, respectively;

FIG. 6 is a schematic view of the protein in a situation where acomposite switch control pocket 120 is formed with portions of theswitch control ligand 106 and the on switch control pocket 102, and witha small molecule 122 in binding relationship with the composite pocket;and

FIG. 7 is a schematic view of the protein in a situation where acombined switch control pocket 124 is formed with portions of the onswitch control pocket 102, the switch control ligand sequence 106, andthe active ATP site 108, and with a small molecule 126 in bindingrelationship with the combined switch control pocket.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a way of rationally developing new smallmolecule modulators which interact with naturally occurring proteins(e.g., mammalian, and especially human proteins) in order to modulatethe activity of the proteins. Novel protein-small molecule adducts arealso provided. The invention preferably makes use of naturally occurringproteins having a conformational property whereby the proteins changetheir conformations in vivo with a corresponding change in proteinactivity. For example, a given enzyme protein in one conformation may bebiologically upregulated, while in another conformation, the sameprotein may be biologically downregulated. The invention preferablymakes use of one mechanism of conformation change utilized by naturallyoccurring proteins, through the interaction of what are termed “switchcontrol ligands” and “switch control pockets” within the protein.

As used herein, “switch control ligand” means a region or domain withina naturally occurring protein and having one or more amino acid residuestherein which are transiently modified in vivo between individual statesby biochemical modification, typically phosphorylation, sulfation,acylation or oxidation. Similarly, “switch control pocket” means aplurality of contiguous or non-contiguous amino acid residues within anaturally occurring protein and comprising residues capable of bindingin vivo with transiently modified residues of a switch control ligand inone of the individual states thereof in order to induce or restrict theconformation of the protein and thereby modulate the biological activityof the protein, and/or which is capable of binding with a non-naturallyoccurring switch control modulator molecule to induce or restrict aprotein conformation and thereby modulate the biological activity of theprotein.

A protein-modulator adduct in accordance with the invention comprises anaturally occurring protein having a switch control pocket with anon-naturally occurring molecule bound to the protein at the region ofsaid switch control pocket, said molecule serving to at least partiallyregulate the biological activity of said protein by inducing orrestricting the conformation of the protein. Preferably, the proteinalso has a corresponding switch control ligand, the ligand interactingin vivo with the pocket to regulate the conformation and biologicalactivity of the protein such that the protein will assume a firstconformation and a first biological activity upon the ligand-pocketinteraction, and will assume a second, different conformation andbiological activity in the absence of the ligand-pocket interaction.

The nature of the switch control ligand/switch control pocketinteraction may be understood from a consideration of schematic FIGS.1-4. Specifically, in FIG. 1, a protein 100 is illustrated in schematicform to include an “on” switch control pocket 102, and “off” switchcontrol pocket 104, and a switch control ligand 106. In addition, theschematically depicted protein also includes an ATP active site 108. Inthe exemplary protein of FIG. 1, the ligand 106 has three amino acidresidues with side chain OH groups 110. The off pocket 104 containscorresponding X residues 112 and the on pocket 102 has Z residues 114.In the exemplary instance, the protein 100 will change its conformationdepending upon the charge status of the OH groups 110 on ligand 106,i.e., when the OH groups are ummodified, a neutral charge is presented,but when these groups are phosphorylated a negative charge is presented.

The functionality of the pockets 102, 104 and ligand 106 can beunderstood from a consideration of FIGS. 2-4. In FIG. 2, the ligand 106is shown operatively interacted with the off pocket 104 such that the OHgroups 110 interact with the X residues 112 forming a part of the pocket104. Such interaction is primarily by virtue of hydrogen bonding betweenthe OH groups 110 and the residues 112. As seen, this ligand/pocketinteraction causes the protein 100 to assume a conformation differentfrom that seen in FIG. 1 and corresponding to the off or biologicallydownregulated conformation of the protein.

FIG. 3 illustrates the situation where the ligand 106 has shifted fromthe off pocket interaction conformation of FIG. 2 and the OH groups 110have been phosphorylated, giving a negative charge to the ligand. Inthis condition, the ligand has a strong propensity to interact with onpocket 102, to thereby change the protein conformation to the on orbiologically upregulated state (FIG. 4). FIG. 4 a illustrates that thephosphorylated groups on the ligand 106 are attracted to positivelycharged residues 114 to achieve an ionic-like stabilizing bond. Notethat in the on conformation of FIG. 4, the protein conformation isdifferent than the off conformation of FIG. 2, and that the ATP activesite is available and the protein is functional as a kinase enzyme.

FIGS. 1-4 illustrate a simple situation where the protein exhibitsdiscrete pockets 102 and 104 and ligand 106. However, in many cases amore complex switch control pocket pattern is observed. FIG. 6illustrates a situation where an appropriate pocket for small moleculeinteraction is formed from amino acid residues taken both from ligand106 and, for example, from pocket 102. This is termed a “compositeswitch control pocket” made up of residues from both the ligand 106 anda pocket, and is referred to by the numeral 120. A small molecule 122 isillustrated which interacts with the pocket 120 for protein modulationpurposes.

Another more complex switch pocket is depicted in FIG. 7 wherein thepocket includes residues from on pocket 102, and ATP site 108 to createwhat is termed a “combined switch control pocket.” Such a combinedpocket is referred to as numeral 124 and may also include residues fromligand 106. An appropriate small molecule 126 is illustrated with pocket124 for protein modulation purposes.

It will thus be appreciated that while in the simple pocket situation ofFIGS. 1-4, the small molecule will interact with the simple pocket 102or 104, in the more complex situations of FIGS. 6 and 7 the interactivepockets are in the regions of the pockets 120 or 124. Thus, broadly thesmall molecules interact “at the region” of the respective switchcontrol pocket.

Materials and Methods General Synthesis of Compounds

In the synthetic schemes of this section, q is 0 or 1. When q=0, thesubstituent is replaced by a synthetically non-interfering group R₇.

Compounds of Formula I wherein Q is taken from Q-1 or Q-2 and Y isalkylene are prepared according to the synthetic route shown in Scheme1.1. Reaction of isothiocyanate 1 with chlorine, followed by addition ofisocyanate 2 affords 3-oxo-thiadiazolium salt 3. Quenching of thereaction with air affords compounds of Formula I-4. Alternatively,reaction of isothiocyanate 1 with isothiocyanate 5 under the reactionconditions gives rise to compounds of Formula I-7. See A. Martinez etal, Journal of Medicinal Chemistry (2002) 45: 1292.

Intermediates 1, 2 and 5 are commercially available or preparedaccording to Scheme 1.2. Reaction of amine 8 with phosgene or a phosgeneequivalent affords isocyanate 2. Similarly, reaction of amine 8 withthiophosgene affords isothiocyanate 5. Amine 8 is prepared bypalladium(0)-catalyzed amination of 9, wherein M is a group capable ofoxidative insertion into palladium(0), according to methodology reportedby S. Buchwald. See M. Wolter et al, Organic Letters (2002) 4:973; B. H.Yang and S. Buchwald, Journal of Organometallic Chemistry (1999)576(1-2):125. In this reaction sequence, P is a suitable amineprotecting group. Use of and removal of amine protecting groups isaccomplished by methodology reported in the literature (ProtectiveGroups in Organic Synthesis, Peter G. M. Wutts, Theodora Greene(Editors) 3rd edition (April 1999) Wiley, John & Sons, Incorporated;ISBN: 0471160199). Starting compounds 9 are commercially available orreadily prepared by one of ordinary skill in the art: See March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure,Michael B. Smith & Jerry March (Editors) 5th edition (January 2001)Wiley John & Sons; ISBN: 0471585890.

Compounds of Formula I wherein Q is taken from Q-1 or Q-2 and Y isalkylene are also available via the synthetic route shown in Scheme 1.3.Reaction of amine 8 with isocyanate or isothiocyanate 2a yields theurea/thiourea 8a which can be cyclized by the addition of chlorocarbonylsulfenyl chloride. See GB1115350 and U.S. Pat. No. 3,818,024, Revankaret. al U.S. Pat. No. 4,093,624, and Klayman et. al JOC 1972, 37(10),1532 for further details. Where R₄ is a readily removable protectinggroup (e.g. R=3,4-d-methoxybenzyl amine), the action of mild, acidicdeprotection conditions such as CAN or TFA will reveal the parent ringsystem of I-4 (X═O) and I-7 (X═S).

I-7 is also available as shown in Scheme 1.4. Condensation of isocyanateor isothiocyanate 2a with amine R₅NH₂ yields urea/thiourea 2b, which,when reacted with chlorocarbonyl sulfenyl chloride according toGB1115350 and U.S. Pat. No. 3,818,024 yields 2c. Where R₄ is a readilyremovable protecting group (e.g. R=3,4-d-methoxybenzyl amine), theaction of mild, acidic deprotection conditions such as CAN or TFA willreveal the parent ring system of 2d. Reaction of 2d with NaH in DMF, anddisplacement wherein M is a suitable leaving group such as chloride,bromide or iodide yields I-4 (X═O) and I-7 (X═S).

Compounds of Formula I wherein Q is taken from Q-1′ or Q-2′ and Y isalkylene are available via the synthetic route shown in Scheme 1.3.Condensation of isocyanate or isothiocyanate 2a with ammonia yieldsurea/thiourea 2e, which, when reacted with chlorocarbonyl sulfenylchloride according to GB 1115350 and U.S. Pat. No. 3,818,024 yields 2f.Reaction of 2f with NaH in DMF, and displacement wherein M is a suitableleaving group such as chloride, bromide or iodide yields I-4′ (X═O) andI-7′ (X═S).

Compounds of Formula I wherein Q is taken from Q-3 or Q-4 and Y isalkylene, are prepared according to the synthetic route shown in Schemes2.1 and 2.2, respectively. Reaction of 12, wherein M is a suitableleaving group, with the carbamate-protected hydrazine 13 affordsintermediate 14. Reaction of 14 with an isocyanate gives rise tointermediate 15. Thermal cyclization of 15 affords1,2,4-triazolidinedione of Formula I-16. By analogy, scheme 2.2illustrates the preparation of 3-thio-5-oxo-1,2,4-triazolidines ofFormula I-18 by reaction of intermediate 14 with an isothiocyanate andsubsequent thermal cyclization.

Intermediates 12 wherein p is 1 are readily available or are prepared byreaction of 19 with carbamates 10 under palladium(0)-catalyzedconditions. M¹ is a group which oxidatively inserts palladium(0),preferably iodo or bromo, and is of greater reactivity than M. Compounds19 are either commercially available or prepared by one of ordinaryskill in the art.

Compounds of Formula I wherein D is taken from Q-3 or Q-4 and Y isalkylene, are also prepared according to the synthetic route shown inScheme 2.4. Oxidation of amine R₄NH₂ to the corresponding hydrazine,condensation with ethyl chloroformate subsequent heating yields1,2,4-triazolidinedione 15a. After the action of NaH in DMF,displacement wherein M is a suitable leaving group such as chloride,bromide or iodide yields I-16 (X═O) and I-18 (X═S).

Compounds of Formula I wherein D is taken from D-3′ or D-4′ and Y isalkylene, are also prepared according to the synthetic route shown inScheme 2.4. When R₅ is a readily removable protecting group (e.g.R=3,4-d-methoxybenzyl amine), the action of mild, acidic deprotectionconditions such as CAN or TFA on 15a will reveal 1,2,4-triazolidinedione15b. After deprotonation of 15b by NaH in DMF, displacement wherein M isa suitable leaving group such as chloride, bromide or iodide yieldsI-16′ (X═O) and I-18′ (X═S).

Compounds of Formula I wherein Q is taken from Q-5 or Q-6 and Y isalkylene are prepared according to the synthetic route shown in Scheme3. Reaction of hydrazine 20 with chlorosulfonylisocyanate and base, suchas triethylamine, gives rise to a mixture of intermediates 21A and 21Bwhich are not isolated but undergo cyclization in situ to affordcompounds of Formulae I-22A and I-22B. Compounds I-22A and I-22B areseparated by chromatography or fractional crystallization. Optionally,compounds I-22A and I-22B can undergo Mitsunobu reaction with alcoholsR₄OH to give compounds of Formulae I-23A and I-23B. Compounds 20 areprepared by acid-catalyzed deprotection of t-butyl carbamates ofstructure 14, wherein R₁₀ is t-butyl.

Compounds of Formula I wherein Q is Q-7 and Y is alkylene are preparedas shown in Scheme 4. Reaction of amine 8 with maleimide 2, wherein M isa suitable leaving group, affords compounds of Formula I-25. Reaction ofcompound 2, wherein M is a group which can oxidatively insert Pd(0), canparticipate in a Heck reaction with maleimide 27, affording compounds ofFormula I-28. Maleimides 24 and 27 are commercially available orprepared by one of ordinary skill in the art.

Compounds of Formula I wherein Q is Q-8 and Y is alkylene are preparedas shown in Scheme 5, according to methods reported by M. Tremblay etal, Journal of Combinatorial Chemistry (2002) 4:429. Reaction ofpolymer-bound activated ester 29 (polymer linkage is oximeactivated-ester) with chlorosulfonylisocyante and t-butanol affordsN-BOC sulfonylurea 30. Subjection of 30 to the Mitsunobu reaction withR₄₀H gives rise to 31. BOC-group removal with acid, preferablytrifluoroacetic acid, and then treatment with base, preferablytriethylamine, provides the desired sulfahydantoin I-32. Optionally,intermediate 30 is treated with acid, preferably trifluoroacetic acid,to afford the N-unsubstituted sulfahydantoin I-33.

Compounds of Formula I wherein Q is Q-8 and Y is alkylene are alsoprepared as shown in Scheme 5a. Amine 8 is condensed with the glyoxalhemiester to yield 31a. Reaction of chlorosulphonyl isocyanate firstwith benzyl alcohol then 31a yields 31b, which after heating yieldsI-32.

Compounds of Formula I wherein Q is taken from Q-8′, are preparedaccording to the synthetic route shown in Scheme 5.2. Formation of 31cby the method of Muller and DuBois JOC 1989, 54, 4471 and itsdeprotonation with NaH/DMF or NaH/DMF and subsequently alkylationwherein M is a suitable leaving group such as chloride, bromide oriodide yields I-32′. Alternatively, I-32′ is also available as shown inScheme 5.3. Mitsunobu reaction of boc-sulfamide amino ethyl ester withalcohol 8b (made by methods analogous to that for amine 8) yields 31c,which after Boc removal with 2N HCl in dioxane is cyclized by the actionof NaH on 31d results in I-32′.

Compounds of Formula I wherein Q is Q-9 and Y is alkylene are preparedas shown in Scheme 6. Reaction of polymer-bound amino acid ester 34 withan isocyanate affords intermediate urea 35. Treatment of 35 with base,preferably pyridine or triethylamine, with optional heating, gives riseto compounds of Formula I-36.

Compounds of Formula I wherein Q is Q-9 and Y is alkylene are alsoprepared as shown in Scheme 6.1. Reaction of aldehyde 8c under reductiveamination conditions with the t-butyl ester of glycine yields 35a.Isocyanate 2a is condensed with p-nitrophenol (or the correspondingR₄NH₂ amine is condensed with p-nitrophenyl chloroformate) to yield thecarbamic acid p-nitrophenyl ester, which when reacted with deprotonated35a and yields the urea that when deprotected with acid yields 35b.Formula I-36 is directly available from 35b by the action of NaH andheat.

Compounds of Formula I wherein Q is taken from Q-9′, are preparedaccording to the synthetic route shown in Scheme 6.2. Formation of 35cby the method described in JP10007804A2 and Zvilichovsky and Zucker,Israel Journal of Chemistry, 1969, 7(4), 547-54 and its deprotonationwith NaH/DMF or NaH/DMF and its subsequent displacement of M, wherein Mis a suitable leaving group such as chloride, bromide or iodide, yieldsI-36′.

Compounds of Formula I wherein Q is Q-10 or Q-11, and Y is alkylene areprepared as shown in Schemes 7.1 and 7.2, respectively. Treatment ofalcohol 37 (Z=O) or amine 37 (Z=NH) with chlorosulfonylisocyanateaffords intermediate carbamate or urea of structure 38. Treatment of 38with an amine of structure HN(R₄)₂ and base, preferably triethylamine orpyridine, gives sulfonylureas of Formula I-39. Reaction ofchlorosulonylisocyanate with an alcohol (Z=O) or amine (Z=NR₄) 40affords intermediate 41. Treatment of 41 with an amine 8 and base,preferably triethylamine or pyridine, gives sulfonylureas of FormulaI-42.

Compounds of Formula I wherein Q is taken from Q-12 are preparedaccording to the synthetic route shown in Scheme 8. Alkylation ofpyridine 43, wherein TIPS is triisopropylsilyl, under standardconditions (K₂CO₃, DMF, R₄—I or Mitsunobu conditions employing R₄—OH)yields pyridine derivative 44 which is reacted with compound 12, whereinM is a suitable leaving group, to afford pyridones of formula I-45.

Compounds of Formula I wherein Q is taken from Q-13 are preparedaccording to the synthetic route shown in Scheme 9. Starting fromreadily available pyridine 46, alkylation under standard conditions(K₂CO₃, DMF, R₄—1 or Mitsunobu conditions employing R₄—OH) yieldspyridine derivative 47. N-alkylation with K₂CO₃, DMF, R₄—I affordspyridones of formula 48. Intermediate 48 is partitioned to undergo aHeck reaction, giving I-49; a Buchwald amination reaction, giving I-51;or a Buchwald Cu(I) catalyzed O-arylation reaction, to give I-52. TheHeck reaction product I-49 may be optionally hydrogenated to afford thesaturated compound I-50. Wherein the phenyl ether R₄ group is methyl,compounds of formula I-49, I-50, I-51, or I-52 are treated with borontribromide or lithium chloride to afford compounds of Formula I-53,wherein R₄ is hydrogen.

Compounds of Formula I wherein Q is taken from Q-14 are preparedaccording to the synthetic route shown in Scheme 10. Starting fromreadily available pyridine 54, alkylation under standard conditions(K₂CO₃, DMF, R₄—1 or Mitsunobu conditions employing R₄—OH) yieldspyridine derivative 55. N-alkylation with K₂CO₃, DMF, R₄—1 affordspyridones of formula 56. Intermediate 5, wherein M is a suitable leavinggroup, preferably bromine or chlorine, is partitioned to undergo a Heckreaction, giving I-57; a Buchwald amination reaction, giving I-59; or aBuchwald Cu(I) catalyzed O-arylation reaction, to give I-60. The Heckreaction product I-57 may be optionally hydrogenated to afford thesaturated compound I-58. Wherein R₄ is methyl, compounds of formulaI-57, I-58, I-59, or I-60 are treated with boron tribromide or lithiumchloride to afford compounds of Formula I-61, wherein R₄ is hydrogen.

Compounds of Formula I wherein Q is taken from Q-15 are preparedaccording to the synthetic routes shown in Schemes 11 and 12. Startingesters 62 are available from the corresponding secoacids via TBS-etherand ester formation under standard conditions. Reaction of protectedsecoester 62 with Meerwin's salt produces the vinyl ether 63 as a pairof regioisomers. Alternatively, reaction of 62 with dimethylamineaffords the vinylogous carbamate 64. Formation of thedihydropyrimidinedione 66 proceeds by condensation with urea 65 withazeotropic removal of dimethylamine or methanol. Dihydropyrimidinedione66 may optionally be further substituted by Mitsunobu reaction withalcohols R₄OH to give rise to compounds 67.

Scheme 12 illustrates the further synthetic elaboration of intermediates67. Removal of the silyl protecting group (TBS) is accomplished bytreatment of 67 with fluoride (tetra-n-butylammonium fluoride or cesiumfluoride) to give primary alcohols 68. Reaction of 68 with isocyanates 2gives rise to compounds of Formula I-69. Alternatively, reaction of 68with [R₆O₂C(NH)_(p)]_(q)-D-E-M, wherein M is a suitable leaving group,affords compounds of Formula I-70. Oxidation of 68 using the Dess-Martinperiodinane (D. Dess, J. Martin, J. Am. Chem. Soc. (1991) 113:7277) ortetra-n-alkyl peruthenate (W. Griffith, S. Ley, Aldrichimica Acta (1990)23:13) gives the aldehydes 71. Reductive amination of 71 with amines 8gives rise to compounds of Formula I-72. Alternatively, aldehydes 71 maybe reacted with ammonium acetate under reductive alkylation conditionsto give rise to the primary amine 73. Reaction of 73 with isocyanates 2affords compounds of Formula I-74.

Compounds of Formula I wherein Q is taken from Q-16 are preparedaccording to the synthetic routes shown in Schemes 13 and 14. Startingesters 75 are available from the corresponding secoacids via TBS-etherand ester formation under standard conditions. Reaction of protectedsecoester 75 with Meerwin's salt produces the vinyl ether 76 as a pairof regioisomers. Alternatively, reaction of 75 with dimethylamineaffords the vinylogous carbamate 77. Formation of thedihydropyrimidinedione 78 proceeds by condensation with urea 65 withazeotropic removal of dimethylamine or methanol. Dihydropyrimidinedione78 may optionally be further substituted by Mitsunobu reaction withalcohols R₄OH to give rise to compounds 79. Compounds of Formulae I-81,I-82, I-84, and I-86 are prepared as shown in Scheme 14 by analogy tothe sequence previously described in Scheme 12.

Alkyl acetoacetates 87 are commercially available and are directlyconverted into the esters 88 as shown in Scheme 15. Treatment of 87 withNaHMDS in THF, followed by quench with formaldehyde and TBSCl (n=1) orQ-(CH₂)n-OTBS (n=24), gives rise to compounds 88.

Compounds of Formula I wherein Q is taken from Q-17 are preparedaccording to the synthetic routes shown in Schemes 16.1 and 16.2, andstarts with the BOC-protected hydrazine 13, which is converted to the1,2-disubstituted hydrazine 89 by a reductive alkylation with a glyoxalderivative mediated by sodium cyanoborohydride and acidic workup.Condensation of 89 with diethyl malonate in benzene under reflux yieldsthe heterocycle 90. Oxidation with N₂O₄ in benzene (see Cardillo,Merlini and Boeri Gazz. Chim. Ital., (1966) 9:8) to thenitromalonohydrazide 91 and further treatment with P₂O₅ in benzene (see:Cardillo, G. et al, Gazz. Chim. Ital. (1966) 9:973-985) yields thetricarbonyl 92. Alternatively, treatment of 90 with Brederick's reagent(t-BuOCH(N(Me₂)₂, gives rise to 93 which is subjected to ozonolysis,with a DMS and methanol workup, to afford the protected tricarbonyl 92.Compound 92 is readily deprotected by the action of CsF in THF to yieldthe primary alcohol 94. Alcohol 94 is optionally converted into theprimary amine 95 by a sequence involving tosylate formation, azidedisplacement, and hydrogenation.

Reaction of 94 with (hetero)aryl halide 26, wherein M is iodo, bromo, orchloro, under copper(I) catalysis affords compounds I-96. Optionaldeprotection of the di-methyl ketal with aqueous acid gives rise tocompounds of Formula I-98. By analogy, reaction of amine 95 with 26under palladium(0) catalysis affords compounds of Formula I-97. Optionaldeprotection of the di-methyl ketal with aqueous acid gives rise tocompounds of Formula I-99.

Compounds of Formula I wherein Q is taken from Q-17 are also preparedaccording to the synthetic route shown in Scheme 16.3. Deprotonation of4,4-dimethyl-3,5-dioxopyrazolidine (95a, prepared according to themethod described in Zinner and Boese, D. Pharmazie 1970, 25(5-6), 309-12and Bausch, M. J. et. al J. Org. Chem. 1991, 56(19), 5643) with NaH/DMFor NaH/DMF and its subsequent displacement of M, wherein M is a suitableleaving group such as chloride, bromide or iodide yields I-99a.

Compounds of Formula I wherein Q is taken from Q-18 are prepared asshown in Schemes 17.1 and 17.2. Aminoesters 100 are subjected toreductive alkylation conditions to give rise to intermediates 101.Condensation of amines 101 with carboxylic acids using an acidactivating reagent such as dicyclohexylcarbodiimide(DCC)/hydroxybenzotriazole (HOBt) affords intermediate amides 102.Cyclization of amides 102 to tetramic acids 104 is mediated by AmberlystA-26 hydroxide resin after trapping of the in situ generated alkoxide103 and submitting 103 to an acetic acid-mediated resin-release.

Scheme 17.2 illustrates the synthetic sequences for convertingintermediates 104 to compounds of Formula I. Reaction of alcohol 104.1with aryl or heteroaryl halide 26 (Q=halogen) under copper(I) catalysisgives rise to compounds of Formula I-105.1. Reaction of amines 104.2 and104.3 with 26 under Buchwald palladium(0) catalyzed amination conditionsaffords compounds of Formulae I-105.2 and I-105.3. Reaction of acetylene104.4 with 26 under Sonogashira coupling conditions affords compounds ofFormula I-105.4. Compounds I-105.4 may optionally be reduced to thecorresponding saturated analogs I-105.5 by standard hydrogenation.

Compounds of Formula I wherein Q is taken from Q-19, Q-20, or Q-21 areprepared as illustrated in Scheme 18. Commercially available Kemp's acid106 is converted to its anhydride 107 using a dehydrating reagent,preferably di-isopropylcarbodiimide (DIC) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). Reaction of 107with amines R₄NH₂ affords the intermediate amides which are cyclized tothe imides 108 by reaction with DIC or EDC. Alternatively, 107 isreacted with amines 8 to afford amides of Formula I-110. Amides I-110may optionally be further reacted with DIC or EDC to give rise tocompounds of Formula I-111. Acid 108 is further reacted with amines 8 togive compounds of Formula I-109.

Compounds of Formula I wherein Q is taken from Q-22 or Q-23 are preparedas shown in Schemes 19.1 through 19.3. Preparation of intermediates 113and 114 are prepared as shown in Scheme 19.1 from di-halo(hetero)aryls112 wherein M₂ is a more robust leaving group than M₁. Reaction of 112with amines 37 (Z=NH) either thermally in the presence of base or bypalladium(0) catalysis in the presence of base and phosphine ligandaffords compounds 113. Alternatively, reaction of 112 with alcohols 37(X═O) either thermally in the presence of base or by copper(I) catalysisin the presence of base affords compounds 114.

Scheme 19.2 illustrates the conversion of intermediates 113 intocompounds of Formula I-115, I-118, or 117. Treatment of 113 with aqueouscopper oxide or an alkaline hydroxide affords compounds of FormulaI-115. Alternatively, treatment of 113 with t-butylmercaptan undercopper(I) catalysis in the presence of ethylene glycol and potassiumcarbonate gives rise to 116 (see F. Y. Kwong and S. L. Buchwald, OrganicLetters (2002) 4:3517. Treatment of the t-butyl sulfide 116 with acidaffords the desired thiols of Formula I-118. Alternatively, 113 may betreated with excess ammonia under pressurized conditions to affordcompound 117.

Scheme 19.3 illustrates the conversion of intermediate 114 intocompounds of Formula I-119, I-122, and 121, by analogy to the sequencedescribed in Scheme 19.2.

Compounds of Formula I wherein q is taken from Q-24, Q-25, or Q-26 areprepared as shown in Scheme 20. Reaction of compounds I-115 or I-119with chlorosulfonylisocyanate, followed by in situ reaction with aminesHN(R₄)₂ gives rise to compounds of Formulae I-123 or I-124. Reaction ofcompounds I-118 or I-122 with a peracid, preferably peracetic acid ortrifluoroperacetic acid, affords compounds of Formula I-125 or I-126.Reaction of compounds 117 or 121 with chlorosulfonylisocyanate, followedby in situ reaction with amines HN(R₄)₂ or alcohols R₄OH, affordscompounds of Formulae I-127, I-128, I-129, or I-130.

Compounds of Formula I wherein Q is taken from Q-27 are prepared asillustrated in Scheme 21. Reductive alkylation of thiomorpholine withaldehydes 131 affords benzylic amines 132, which are then subjected toperacid oxidation to give rise to the thiomorpholine sulfones 133 (seeC. R. Johnson et al, Tetrahedron (1969) 25: 5649). Intermediates 133 arereacted with amines 8 (Z=NH₂) under Buchwald palladium-catalyzedamination conditions to give rise to compounds of Formula I-134.Alternatively, compounds 133 are reacted with alcohols 8 (Z=OH) underBuchwald copper(I) catalyzed conditions to afford compounds of FormulaI-135. Alternatively, intermediates 133 are reacted with alkenes underpalladium(0)-catalyzed Heck reaction conditions to give compounds ofFormula I-136. Compounds I-136 are optionally reduced to thecorresponding saturated analogs I-137 by standard hydrogenationconditions or by the action of diimide.

Compounds of Formula I wherein Q is taken from Q-27 are also prepared asillustrated in Scheme 21.1. Aldehyde 8c is reductively aminated withammonia, and the resultant amine condensed with divinyl sulphone toyield I-134. Intermediate 134a is also available by reduction of amide8d under a variety of standard conditions.

More generally, amines 134c are available via the reduction of amides134b as shown Scheme 21.2. The morpholine amide analogues 134d andmorpholine analogues 134e are so available as shown in Scheme 21.2.

Compounds of Formula I wherein Q is taken from Q-28 or Q-29 are preparedaccording to the sequences illustrated in Scheme 22. Readily availableamides 138 are reacted with chlorosulfonylisocyanate to giveintermediates 140, which are reacted in situ with amines HN(R₄)₂ oralcohols R₄OH to afford compounds of Formulae I-141 or I-142,respectively. Alternatively, amides 138 are reacted withsulfonylchlorides to give compounds of Formula I-139.

Compounds of Formula I wherein Q is taken from Q-30 are prepared asshown in Scheme 23. Readily available N-BOC anhydride 143 (see S. Chenet al, J. Am. Chem. Soc. (1996) 118:2567) is reacted with amines HN(R₄)₂or alcohols R₆OH to afford acids 144 or 145, respectively. Intermediates144 or 145 are further reacted with amines HN(R₄)₂ in the presence of anacid-activating reagent, preferably PyBOP and di-isopropylethylamine, togive diamides 146 or ester-am ides 147. Intermediate 145 is converted tothe diesters 148 by reaction with an alkyl iodide in the presence ofbase, preferably potassium carbonate. Intermediates 146-148 are treatedwith HCl/dioxane to give the secondary amines 149-151, which are thencondensed with acids 152 in the presence of PyBOP anddiisopropylethylamine to give compounds of Formula I-153.

Compounds of Formula I wherein Q is taken from Q-31 or Q-32 are preparedaccording to the sequences illustrated in Scheme 24. Treatment ofreadily available sulfenamides 154 with amines 37 (Z=NH), alcohols 37(Z=O), or alkenes 37 (Z=—CH═CH₂), gives rise to compounds of FormulaI-155. Treatment of sulfenamides I-155 with iodosobenzene in thepresence of alcohols R&OH gives rise to the sulfonimidates of FormulaI-157 (see D. Leca et al, Organic Letters (2002) 4:4093). Alternatively,compounds I-155 (Z=—CH═CH) may be optionally reduced to the saturatedanalogs I-156 (Z=CH₂—CH₂—), which are converted to the correspondingsulfonimidates I-157.

Treatment of readily available sulfonylchlorides 154.1 with aminesHN(R₄)₂ and base gives rise to compounds of Formula I-154.2.

Compounds of Formula I wherein Q is taken from Q-33 are prepared asshown in Scheme 25. Readily available nitriles 158 are reacted withamines 37 (Z=NH), alcohols 37 (Z=O), or alkenes 37 (Z=—CH═CH₂) to affordcompounds of Formula I-159. Compounds I-159 (wherein Z=CH═CH—) areoptionally reduced to their saturated analogs I-160 by standardcatalytic hydrogenation conditions. Treatment of compounds I-159 orI-160 with a metal azide (preferably sodium azide or zinc azide) givesrise to tetrazoles of Formula I-161.

Compounds of Formula I wherein Q is taken from Q-34 are prepared asshown in Scheme 26. Readily available esters 162 are reacted with amines37 (Z=NH), alcohols 37 (Z=O), or alkenes 37 (Z=—CH═CH₂) to affordcompounds of Formula I-163. Compounds I-163 (wherein Z is —CH═CH—) areoptionally converted to the saturated analogs I-164 by standardhydrogenation conditions. Compounds I-163 or I-164 are converted to thedesired phosphonates I-165 by an Arbuzov reaction sequence involvingreduction of the esters to benzylic alcohols, conversion of the alcoholsto the benzylic bromides, and treatment of the bromides with atri-alkylphosphite. Optionally, phosphonates I-165 are converted to thefluorinated analogs I-166 by treatment with diethylaminosulfurtrifluoride (DAST).

Compounds of Formula I wherein Q is taken from Q-35 are preparedaccording to Scheme 27. Readily available acid chlorides 167 are reactedwith oxazolidones in the presence of base to afford the N-acyloxazolidinones 168. Intermediate 168 are reacted with amines 37 (Z=NH),alcohols 37 (Z=O), or alkenes 37 (Z=—CH═CH₂) to afford the N-acyloxazolidinones of Formula I-169. Compounds I-169 (wherein Z is —CH═CH—)are optionally converted to the saturated analogs I-170 under standardhydrogenation conditions.

Compounds of Formula I wherein Q is taken from Q-35 are also prepared asillustrated in Scheme 27.1. Intermediate 8a, wherein M is a suitableleaving group such as chloride, bromide or iodide, is refluxed withtriethyl phosphite and the resulting phosphoryl intermediate saponifiedunder mild conditions to yield I-165.

Compounds of Formula I wherein Q is taken from Q-36 are prepared asillustrated in Schemes 28.1 and 28.2. Reductive alkylation of thet-butylsulfide substituted piperazines with the readily availablealdehydes 131 gives rise to the benzylic piperazines 171. Intermediates171 are reacted with amines 37 (Z=NH), alcohols 37 (Z=O), or alkenes 37(Z=—CH═CH₂) to give compounds 172, 13 or 174, respectively. Optionally,intermediates 174 are converted to the saturated analogs 175 understandard hydrogenation conditions.

Scheme 28.2 illustrates the conversion of intermediate t-butylsulfides172-175 to the sulfonic acids, employing a two step process involvingacid-catalyzed deprotection of the t-butyl sulfide to the correspondingmercaptans, and subsequent peracid oxidation (preferably with peraceticacid or trifluoroperacetic acid) of the mercaptans to the desiredsulfonic acids of Formula I-176.

In some instances a hybrid p38-alpha kinase inhibitor is prepared whichalso contains an ATP-pocket binding moiety or an allosteric pocketbinding moiety R₁—X-A. The synthesis of functionalized intermediates offormula R₁—X-A are accomplished as shown in Scheme 29. Readily availableintermediates 177, which contain a group M capable of oxidative additionto palladium(0), are reacted with amines 178 (X═NH) under Buchwald Pd(0)amination conditions to afford 179. Alternatively amines or alcohols 178(X═NH or O) are reacted thermally with 177 in the presence of base undernuclear aromatic substitution reaction conditions to afford 179.Alternatively, alcohols 178 (X═O) are reacted with 177 under Buchwaldcopper(I)-catalyzed conditions to afford 179. In cases where p=1, thecarbamate of 179 is removed, preferably under acidic conditions when R₆is t-butyl, to afford amines 180. In cases where p=0, the esters 179 areconverted to the acids 181 preferably under acidic conditions when R₆ ist-butyl.

Another sequence for preparing amines 180 is illustrated in Scheme 30.Reaction of amines or alcohols 178 with nitro(hetero)arenes 182 whereinM is a leaving group, preferably M is fluoride, or M is a group capableof oxidative insertion into palladium(0), preferably M is bromo, chloro,or iodo, gives intermediates 183. Reduction of the nitro group understandard hydrogenation conditions or treatment with a reducing metal,such as stannous chloride, gives amines 180.

In instances when hybrid p38-alpha kinase inhibitors are prepared,compounds of Formula I-184 wherein q is 1 may be converted to aminesI-185 (p=1) or acids I-186 (p=0) by analogy to the conditions describedin Scheme 29. Compounds of Formula I-184 are prepared as illustrated inprevious schemes 1.1, 2.1, 2.2, 3, 4, 5, 6, 7.1, 7.2, 8, 9, 10, 12, 14,16.2, 17.2, 18, 19.1, 19.2, 19.3, 20, 21, 22, 23, 24, 25, 26, 27, or28.2.

The preparation of inhibitors of Formula I which contain an amidelinkage CO—NH— connecting the oxyanion pocket binding moieties andR₁—X-A moieties are shown in Scheme 32. Treatment of acids 181 with anactivating agent, preferably PyBOP in the presence ofdi-iso-propylethylamine, and amines I-185 gives compounds of Formula I.Alternatively, retroamides of Formula I are formed by treatment of acidsI-186 with PyBOP in the presence of di-iso-propylethylamine and amines180.

The preparation of inhibitors of Formula I which contain an urea linkageNH—CO—NH— connecting the oxyanion pocket binding moieties and the R₁—X-Amoieties are shown in Scheme 33. Treatment of amines I-185 withp-nitrophenyl chloroformate and base affords carbamates 187. Reaction of187 with amines 180 gives ureas of Formula I.

Alternatively, inhibitors of Formula I which contain an urea linkageNH—CO—NH— connecting the oxyanion pocket binding moieties and the R₁—X-Amoieties are prepared as shown in Scheme 33. Treatment of amines 180with p-nitrophenyl chloroformate and base affords carbamates 188.Reaction of 188 with amines I-185 gives ureas of Formula I.

The preparation of inhibitors of Formula I.B can be generallyaccomplished starting from a variety of readily availablebeta-ketonitriles 189, wherein R₄₀ is alkyl, phenyl, or perfluoroalkyl.As illustrated in Scheme 35, reaction of 189 with an alcohol R₄OH,preferably methanol or ethanol, under anhydrous acidic conditions,preferably anhydrous HCl, leads to the formation of imidates 190.Reaction of 190 with acyl chlorides, isocyanates,para-nitrophenylcarbamates, or substituted chloroformates in thepresence of a base, preferably pyridine, triethylamine,di-iso-propylethylamine, Barton's base, or an alkali metal carbonate,affords key intermediates 191 and 192 as a mixture of tautomers, whereinT is alkylene, NH, O, or when T is absent, then the carbonyl side chainand A are connected by a direct bond.

The mixture of tautomers 191/192 are not separated from each other, butare reacted as a mixture with a substituted hydrazine 193 wherein the Qmoiety is optionally protected by a protecting group that diminishes itsreactivity with the 191/192 mixture. This cyclodehydration reaction isperformed in the presence of base, acid catalysis, or under neutralconditions optionally in the presence of a dehydrating agent to affordthe desired pyrazoles 194. Preferable reaction solvents includedichloromethane, ethyl acetate, acetonitrile, or an alcoholic solventtaken from methanol, ethanol, or 2-propanol.

The reaction sequence initiating from 190 and yielding 194 may takeplace as two separate reactions, wherein the tautomeric mixture 191/192is isolated, and then in a second reaction step this 191/192 mixture isreacted with a substituted hydrazine 193 to afford the desired pyrazoles194. Alternatively, the reaction sequence initiating from 190 andyielding 194 may take place in a one-pot procedure, without isolation ofthe intermediate 191/192 mixture.

In a further modification, the reaction sequence initiating from 190 andyielding 194 may take place in a parallel array format, whereinphase-trafficking reagents, including scavenging reagents, are utilizedto allow purification and isolation of intermediates and products.Scheme 36 illustrates this modification. Excess imidate 190 is reactedwith a limiting amount of electrophile in the presence of apolymer-supported base 195 to afford the acylated imidates 191/192 as amixture of tautomers. The crude mixture of 191/192 is optionallypurified by incubation with a polymer-supported electrophile 196,preferably a polymer-supported isocyanate or acid chloride. Reaction of196 with any remaining imidate 190 sequesters this imidate aspolymer-supported 197. Filtration gives purified 191/192. In the secondstep, purified acylated imidates 191/192 are reacted with thesubstituted hydrazines 193 to afford desired crude products 194. Apolymer-supported hydrazine 198 is optionally utilized to scavenge anyremaining 191/192 from solution phase as derivatized 199. Filtrationgives rise to purified desired pyrazoles 194.

Scheme 37 illustrates the preparation of compounds wherein Q is Q-40.Readily available amine 200, wherein P is a suitable amine-protectinggroup or a group convertible to an amine group, is reacted withp-nitrophenyl chloroformate to give rise to carbamate 201. Intermediate201 is reacted with a substituted amino acid ester with a suitable baseto afford urea 202. Further treatment with base results in cyclizationto afford hydantoin 203. The protecting group P is removed to afford thekey amine-containing intermediate 204. Alternatively, if P is a nitrogroup, then 203 is converted to 204 under reducing conditions such asiron/HCl, tin(II) chloride, or catalytic hydrogenation. Amine 204 isconverted to 205A by reaction with an isocyanate; 204 is converted toamide 205B by reaction with an acid chloride, acid anhydride, or asuitable activated carboxylic acid in the presence of a suitable base;204 is converted to carbamate 205C by reaction with a substituted alkylor aryl chloroformate in the presence of a suitable base.

Scheme 38 illustrates the synthesis of key substituted hydrazine 210.This hydrazine can be converted into compounds of formula I.B using themethods previously outlined in Schemes 35 and 36. The nitrophenylsubstituted amine 206 is reacted with p-nitrophenyl chloroformate togive rise to carbamate 207. Reaction of 207 with a suitable amino acidester affords urea 208, which is cyclized under basic conditions to givehydantoin 209. Reduction of the nitro group of 209, diazotization of theresulting amine, and reduction of the diazonium salt affords keyhydrazine 210.

Scheme 39 illustrates the synthesis of key substituted hydrazines 213and 216 utilized to prepare compounds of formula I.B wherein Q is Q-42and G is oxygen. Nitrophenol 211 is reacted with an alpha-hydroxy acid,wherein R₄₂ is H or alkyl and R₄₃ is alkyl, under Mitsunobu reactionconditions to give 212; alternatively 211 is reacted under basicconditions with a carboxylic acid ester containing a displaceable Q_(x)group to afford 212. Conversion of 212 to the hydrazine 213 isaccomplished by standard procedures as described above.

Alternatively, the ester group of 212 is hydrolyzed to afford carboxylicacid 214, which is reacted with an amine NH(R₄)₂ in the presence of acoupling reagent, preferably EDC/HOBT, to give amide 215. Conversion of215 to the substituted hydrazine 216 is accomplished by standardprocedures. Hydrazines 213 and 216 can be converted into compounds offormula I.B using the methods previously outlined in Schemes 35 and 36.

Scheme 40 illustrates the synthesis of key substituted hydrazines 219and 222, utilized to prepare compounds of formula I.B wherein Q is Q-42and G is methylene. Nitrophenyl bromide 217 is reacted with analpha-beta unsaturated ester using Pd(0) catalyzed Heck reactionconditions, to afford ester 218. This intermediate is converted to thesubstituted hydrazine 219 by standard procedures involving concomitantreduction of the alpha-beta unsaturated bond. Alternatively, ester 218is hydrolyzed to the carboxylic acid 220, which is reacted with an amineNH(R₄)₂ in the presence of a coupling reagent, preferably EDC/HOBT, togive amide 221. Conversion of 221 to the substituted hydrazine 222 isaccomplished by standard procedures. Hydrazines 219 and 222 can beconverted into compounds of formula I.B using the methods previouslyoutlined in Schemes 35 and 36.

Scheme 41 illustrates an alternative synthesis of key substitutedhydrazines 225 and 228, utilized to prepare compounds of formula I.Bwherein Q is Q-42, G is methylene, and one or both of R₄₂ arecarbon-containing substituents. Nitrobenzyl acetate 223 is reacted witha substituted silylketene acetal to afford ester 224. This intermediateis converted to the substituted hydrazine 225 by standard procedures.Alternatively, ester 223 is hydrolyzed to the carboxylic acid 226, whichis reacted with an amine NH(R₄)₂ in the presence of a coupling reagent,preferably EDC/HOBT, to give amide 227. Conversion of 227 to thesubstituted hydrazine 228 is accomplished by standard procedures.Hydrazines 225 and 228 can be converted into compounds of formula I.Busing the methods previously outlined in Schemes 35 and 36.

Scheme 42 illustrates an alternative synthesis of key substitutedhydrazines 231 and 234, utilized to prepare compounds of formula I.Bwherein Q is Q-42 and G is NH. Iodoaniline 229 is reacted with analpha-keto ester under reductive amination conditions, preferably sodiumtriacetoxyborohydride, to afford ester 230. This intermediate isconverted to the substituted hydrazine 231 by Cu(I)-catalyzed reactionwith N-BOC hydrazine. Alternatively, ester 231 is hydrolyzed to thecarboxylic acid 232, which is reacted with an amine NH(R₄)₂ in thepresence of a coupling reagent, preferably EDC/HOBT, to give amide 233.Conversion of 233 to the substituted hydrazine 234 is accomplished byCu(I)-catalyzed reaction with N-BOC hydrazine. Hydrazines 231 and 234can be converted into compounds of formula I.B using the methodspreviously outlined in Schemes 35 and 36, after acid-catalyzed removalof the hydrazine N-BOC protecting group, preferably with trifluoroaceticacid or HCl-dioxane.

Scheme 43 illustrates an alternative synthesis of key substitutedhydrazine 239 utilized to prepare compounds of formula I.B wherein Q isQ-42, G is oxygen, and X is taken from piperidinyl, piperazinyl,thiomorpholino sulfone, or 4-hydroxypiperinyl. Iodophenol 235 is reactedwith an alpha-hydroxy acid under Mitsunobu reaction conditions to give236; alternatively 235 is reacted under basic conditions with acarboxylic acid ester containing a displaceable Q_(x) , group to afford236. Ester 236 is hydrolyzed to the carboxylic acid 237 which is reactedwith an amine X—H in the presence of a coupling reagent, preferablyEDC/HOBT, to give amide 238. Conversion of 238 to the substitutedhydrazine 239 is accomplished by Cu(I)-catalyzed reaction with N-BOChydrazine. Hydrazine 239 can be converted into compounds of formula I.Busing the methods previously outlined in Schemes 35 and 36, afteracid-catalyzed removal of the hydrazine N-BOC protecting group,preferably with trifluoroacetic acid or HCl-dioxane.

Scheme 44 illustrates an alternative synthesis of key substitutedhydrazine 241, utilized to prepare compounds of formula I.B wherein Q isQ-42, G is NH, and X is taken from piperidinyl, piperazinyl,thiomorpholino sulfone, or 4-hydroxypiperinyl. Carboxylic acid 237 isreacted with an amine X—H in the presence of a coupling reagent,preferably EDC/HOBT, to give amide 240. Conversion of 240 to thesubstituted hydrazine 241 is accomplished by Cu(I)-catalyzed reactionwith N-BOC hydrazine. Hydrazine 241 can be converted into compounds offormula I.B using the methods previously outlined in Schemes 35 and 36,after acid-catalyzed removal of the hydrazine N-BOC protecting group,preferably with trifluoroacetic acid or HCl-dioxane.

Scheme 45 illustrates an alternative synthesis of key substitutedhydrazine 246, utilized to prepare compounds of formula I.B wherein Q isQ-42, G is methylene, and X is taken from piperidinyl, piperazinyl,thiomorpholino sulfone, or 4-hydroxypiperinyl. Iodobenzyl acetate 242 isreacted with a substituted silylketene acetal to afford ester 243. Ester243 is hydrolyzed to the carboxylic acid 244 which is reacted with anamine X—H in the presence of a coupling reagent, preferably EDC/HOBT, togive amide 245. Conversion of 245 to the substituted hydrazine 246 isaccomplished by Cu(I)-catalyzed reaction with N-BOC hydrazine. Hydrazine246 can be converted into compounds of formula I.B using the methodspreviously outlined in Schemes 35 and 36, after acid-catalyzed removalof the hydrazine N-BOC protecting group, preferably with trifluoroaceticacid or HCl-dioxane.

Scheme 46 illustrates an alternative synthesis of key substitutedhydrazines 248, 252, and 255, utilized to prepare compounds of formulaI.B wherein Q is Q-47 or Q-48. Nitrophenol 211 is reacted with asubstituted alcohol under Mitsunobu reaction conditions to afford 247;alternatively 211 is alkylated with R₄-Q_(x), wherein Q, is a suitableleaving group, under basic reaction conditions, to give rise to 247.Conversion of 247 to the substituted hydrazine 248 is accomplished understandard conditions.

The nitrobenzoic acid 249 is converted to the acid fluoride 250 byreaction with a fluorinating reagent, preferably trifluorotriazine.Treatment of acid fluoride 250 with a nucleophilic fluoride source,preferably cesium fluoride and tetra-n-butylammonium fluoride, affordsthe alpha-alpha-difluorosubstituted carbinol 251. Conversion of 251 tothe substituted hydrazine 252 is accomplished under standard conditions.

Nitrobenzaldehyde 253 is reacted with trimethylsilyltrifluoromethane(TMS-CF₃) and tetra-n-butylammonium fluoride to give rise totrifluoromethyl-substituted carbinol 254. Conversion of 254 to thesubstituted hydrazine 255 is accomplished under standard conditions.Hydrazines 248, 252, and 255 can be converted into compounds of formulaI.B using the methods previously outlined in Schemes 35 and 36.

Scheme 47 illustrates the preparation of compounds of formula I.Bwherein Q is Q-59. p-Nitrophenylcarbamate 201 is reacted with asubstituted alpha-hydroxy ester with a suitable base to afford carbamate256. Further treatment with base results in cyclization to affordoxazolidinedione 257. The protecting group P is removed to afford thekey amine-containing intermediate 258; alternatively, if P is a nitrogroup, then 257 is converted to 258 under reducing conditions such asiron/HCl, tin(II) chloride, or catalytic hydrogenation. Amine 258 isconverted to 259A by reaction with an isocyanate wherein T1 is alkyleneor a direct bond connecting A and the carbonyl moiety; 258 is convertedto amide 259B by reaction with an acid chloride, acid anhydride, or asuitable activated carboxylic acid in the presence of a suitable base;258 is converted to carbamate 259C by reaction with a substituted alkylor aryl chloroformate in the presence of a suitable base.

Scheme 48 illustrates an alternative approach to the preparation ofcompounds of formula I.B wherein Q is Q-59. Amine 260 is reacted withp-nitrophenylchloroformate under basic conditions to give rise tocarbamate 261. This intermediate is reacted with an alpha-hydroxy esterin the presence of base to afford carbamate 262. Further treatment withbase converts 262 into the oxazolidinedione 263. Conversion of 263 tothe substituted hydrazine 264 is accomplished by standard procedures.Hydrazine 264 can be converted into compounds of formula I.B using themethods previously outlined in Schemes 35 and 36.

Scheme 49 illustrates the approach to the preparation of compounds offormula I.B wherein Q is Q-57. Amine 265 is reacted withp-methoxybenzylisocyanate under standard conditions to give rise to urea266. This intermediate is reacted with an oxalyl chloride in thepresence of base to afford trione 267. Conversion of 267 to thesubstituted hydrazine 268 and removal of the p-methoxybenzyl protectinggroup is accomplished by standard procedures. Hydrazine 264 can beconverted into compounds of formula I.B using the methods previouslyoutlined in Schemes 35 and 36.

Scheme 50 illustrates an approach to the preparation of compounds offormula I.B wherein Q is Q-56. Amine 269 is reacted withp-methoxybenzylsulfonylchloride under standard conditions to give riseto sulfonylurea 270. This intermediate is reacted with an oxalylchloride in the presence of base to afford the cyclic sulfonyl urea 271.Conversion of 271 to the substituted hydrazine 272 and removal of thep-methoxybenzyl protecting group is accomplished by standard procedures.Hydrazine 272 can be converted into compounds of formula I.B using themethods previously outlined in Schemes 35 and 36.

Scheme 51 illustrates an approach to the preparation of compounds offormula I.B wherein Q is Q-58. Amine 273 is reacted with a cyclicanhydride e.g. succinic anhydride in the presence of base under standardconditions to give rise to imide 274. Conversion of 274 to thesubstituted hydrazine 275 is accomplished by standard procedures.Hydrazine 275 can be converted into compounds of formula I.B using themethods previously outlined in Schemes 35 and 36.

Scheme 52 illustrates an approach to the preparation of compounds offormula I.B wherein Q is Q-54 or Q-55. Carboxylic acid 276 is convertedto protected amine 279 under standard conditions, which can besubsequently converted to hydrazine 280 by standard procedures.Hydrazine 280 can be converted into compounds of formula I.B using themethods previously outlined in Schemes 35 and 36 to yield protectedamine 283 which is readily deprotected to yield amine 284. Reaction ofamine 284 with CDI and amine (R₄)₂NH yields 285 (Q=Q-54). Reaction ofamine 284 with the indicated sulfamoylchloride derivative yields 286(Q=Q-55).

Scheme 53 illustrates an approach to the preparation of compounds offormula I.B wherein Q is Q-49, Q-50 or Q-51. Protected amine 287(available by several literature procedures) is converted to deprotectedhydrazine 288 is accomplished by standard procedures. Hydrazine 288(Q=Q-49) can be converted into compounds of formula I.B using themethods previously outlined in Schemes 35 and 36. Amine 287 can bedeprotected by TFA to yield amine 289 which can be subsequentlyconverted amide 290. Amide 290 is converted to hydrazine 291 (Q=Q-50) bystandard procedures, which can be subsequently converted into compoundsof formula I.B using the methods previously outlined in Schemes 35 and36. Alternatively, amine 289 can be reacted with CDI and amine (R₄)₂NHto yield urea 292 (Q=Q-51). Urea 292 is converted to hydrazine 293(Q=Q-51) by standard procedures, which can be subsequently convertedinto compounds of formula I.B using the methods previously outlined inSchemes 35 and 36.

Scheme 54 illustrates an approach to the preparation of compounds offormula I.B wherein Q is Q-52 and Q-53. Protected amine 294 (availableby several literature procedures) is converted to protected hydrazine295 is accomplished by standard procedures. Hydrazine 295 (Q=Q-49) canbe converted into compounds of formula I.B to yield protected amine 298which is readily deprotected to yield amine 299. Reaction of amine 299with chlorosulfonylisocyanate followed by amine (R₄)₂NH yields 300(Q=Q-52). Alternatively, reaction of chlorosulfonylisocyanate and amine(R₄)₂NH followed by amine 299 yields 301 (Q=Q-53).

Scheme 55 illustrates an approach to the preparation of compounds offormula I.B wherein Q is Q-36. Amine 302 is reacted with CDI and amineR₄NH₂ to yield 303, which is reacted with chlorocarbonylsulfenylchloride to yield thiadiazolidinedione 304. Conversion of 304 tothe substituted hydrazine 305 is accomplished by standard procedures.Hydrazine 305 can be converted into compounds of formula I.B using themethods previously outlined in Schemes 35 and 36.

Scheme 56 illustrates an approach to the preparation of compounds offormula I.B wherein Q is Q-37, Q-38 or Q-39. Imides 309a, 309b, and 312are all available via several literature methods, and are each able tobe alkylated with chloride 306 to yields intermediates 307, 310 and 313respectively. Intermediates 307, 310 and 313 are respectively convertedto hydrazines 308 (Q=Q-37), 311 (Q=Q-38), and 314 (Q=Q-39) by standardprocedures.

Scheme 57 illustrates an alternative preparation of compounds wherein Qis Q-37. Readily available amine 315, wherein P is a suitableamine-protecting group or a group convertible to an amine group, isreacted with SO₂Cl₂ to give rise to sulfonyl chloride 316. Intermediate316 is reacted with a substituted amino acid ester with a suitable baseto afford sulfonylurea 317. Further treatment with base results incyclization to afford sulfohydantoin 318. The protecting group P isremoved to afford the key amine-containing intermediate 319.Alternatively, if P is a nitro group, then 318 is converted to 319 underreducing conditions such as iron/HCl, tin(II) chloride, or catalytichydrogenation. Amine 319 is converted to 320A by reaction with anisocyanate; 319 is converted to amide 320B by reaction with an acidchloride, acid anhydride, or a suitable activated carboxylic acid in thepresence of a suitable base; 319 is converted to carbamate 320C byreaction with a substituted alkyl or aryl chloroformate in the presenceof a suitable base.

Scheme 58 illustrates an alternative synthesis of key substitutedhydrazine 325 of compounds wherein Q is Q-37. This hydrazine can beconverted into compounds of formula I.B using the methods previouslyoutlined in Schemes 35 and 36. The amine 321 is reacted with SO₂Cl₂ togive rise to sulfonyl chloride 322. Reaction of 322 with a suitableamino acid ester affords sulfonylurea 323, which is cyclized under basicconditions to give sulfohydantoin 324. Reduction of the nitro group of324, diazotization of the resulting amine, and reduction of thediazonium salt affords key hydrazine 325.

Scheme 59 illustrates an alternative preparation of compounds wherein Qis Q-38. Readily available amine 326, wherein P is a suitableamine-protecting group or a group convertible to an amine group, isreacted with SO₂Cl₂ to give rise to sulfonyl chloride 327. Intermediate327 is reacted with a substituted hydrazide ester with a suitable baseto afford sulfonylurea 328. Further treatment with base results incyclization to afford sulfotriazaolinedione 329. The protecting group Pis removed to afford the key amine-containing intermediate 330.Alternatively, if P is a nitro group, then 329 is converted to 330 underreducing conditions such as iron/HCl, tin(II) chloride, or catalytichydrogenation. Amine 330 is converted to 331A by reaction with anisocyanate; 330 is converted to amide 331B by reaction with an acidchloride, acid anhydride, or a suitable activated carboxylic acid in thepresence of a suitable base; 330 is converted to carbamate 331C byreaction with a substituted alkyl or aryl chloroformate in the presenceof a suitable base.

Scheme 60 illustrates an alternative synthesis of key substitutedhydrazine 336 of compounds wherein Q is Q-38. This hydrazine can beconverted into compounds of formula I.B using the methods previouslyoutlined in Schemes 35 and 36. The amine 332 is reacted with SO₂Cl₂ togive rise to sulfonyl chloride 333. Reaction of 333 with a substitutedhydrazide ester affords sulfonylurea 334, which is cyclized under basicconditions to give sulfotriazaolinedione 335. Reduction of the nitrogroup of 335, diazotization of the resulting amine, and reduction of thediazonium salt affords key hydrazine 336.

Scheme 61 illustrates the preparation of compounds wherein Q is Q-39.Readily available amine 337, wherein P is a suitable amine-protectinggroup or a group convertible to an amine group, is reacted withp-nitrophenyl chloroformate to give rise to carbamate 338. Intermediate338 is reacted with a substituted amino acid ester with a suitable baseto afford urea 339. Further treatment with base results in cyclizationto afford triazolinedione 340. The protecting group P is removed toafford the key amine-containing intermediate 341. Alternatively, if P isa nitro group, then 340 is converted to 341 under reducing conditionssuch as iron/HCl, tin(II) chloride, or catalytic hydrogenation. Amine341 is converted to 342A by reaction with an isocyanate; 341 isconverted to amide 342B by reaction with an acid chloride, acidanhydride, or a suitable activated carboxylic acid in the presence of asuitable base; 341 is converted to carbamate 342C by reaction with asubstituted alkyl or aryl chloroformate in the presence of a suitablebase.

Scheme 62 illustrates an alternative synthesis of key substitutedhydrazine 347 of compounds wherein Q is Q-39. This hydrazine can beconverted into compounds of formula I.B using the methods previouslyoutlined in Schemes 35 and 36. The nitrophenyl substituted amine 343 isreacted with p-nitrophenyl chloroformate to give rise to carbamate 344.Reaction of 344 with a suitable amino acid ester affords urea 345 whichis cyclized under basic conditions to give triazolinedione 346.Reduction of the nitro group of 346, diazotization of the resultingamine, and reduction of the diazonium salt affords key hydrazine 347.

Scheme 63 illustrates the synthesis of compounds wherein Q is Q-43.Morphiline 348 is alkylated with protected bromohydrine. Removal of thealcohol protecting group yields intermediate 349, which can be oxidizedto aldehyde 350. When G=NH, iodoaniline 351 is reacted with 350 underreductive amination conditions, preferably sodium triacetoxyborohydride,to afford intermediate 352. This intermediate is converted to thesubstituted hydrazine 353 by Cu(I)-catalyzed reaction with N-BOChydrazine. When G=O, iodophenol 355 is either alkylated with 354 orreacted under Mitsunobu conditions with alcohol 349 to yieldintermediate 356. This intermediate is converted to the substitutedhydrazine 353 by Cu(I)-catalyzed reaction with N-BOC hydrazine.

Scheme 64 illustrates the synthesis of compounds wherein Q is Q-43,G=CH₂. Nitroacid 358 (readily available by anyone with normal skills inthe art) is reacted with morphiline to yield amide 359, which uponreduction to the amine and conversion of the nitro group under standardconditions results in hydrazine 360. This hydrazine can be convertedinto compounds of formula I.B using the methods previously outlined inSchemes 35 and 36.

Scheme 65 illustrates the synthesis of compounds wherein Q is Q-44.N-methyl piperazine 361 is alkylated with protected bromohydrine.Removal of the alcohol protecting group yields intermediate 362, whichcan be oxidized to aldehyde 363. When G=NH, iodoaniline 364 is reactedwith 363 under reductive amination conditions, preferably sodiumtriacetoxyborohydride, to afford intermediate 365. This intermediate isconverted to the substituted hydrazine 366 by Cu(I)-catalyzed reactionwith N-BOC hydrazine. When G=O, iodophenol 368 is either alkylated with367 or reacted under Mitsunobu conditions with alcohol 362 to yieldintermediate 369. This intermediate is converted to the substitutedhydrazine 370 by Cu(I)-catalyzed reaction with N-BOC hydrazine.

Scheme 66 illustrates the synthesis of compounds wherein Q is Q-44,G=CH₂. Nitroacid 371 (readily available by anyone with normal skills inthe art) is reacted with N-methyl piperazine to yield amide 372, whichupon reduction to the amine and conversion of the nitro group understandard conditions results in hydrazine 373. This hydrazine can beconverted into compounds of formula I.B using the methods previouslyoutlined in Schemes 35 and 36.

Scheme 67 illustrates the synthesis of compounds wherein Q is Q-45.Thiomorpholine sulphone 374 is alkylated with protected bromohydrine.Removal of the alcohol protecting group yields intermediate 375, whichcan be oxidized to aldehyde 376. When G=NH, iodoaniline 377 is reactedwith 376 under reductive amination conditions, preferably sodiumtriacetoxyborohydride, to afford intermediate 378. This intermediate isconverted to the substituted hydrazine 379 by Cu(I)-catalyzed reactionwith N-BOC hydrazine. When G=O, iodophenol 380 is either alkylated with381 or reacted under Mitsunobu conditions with alcohol 375 to yieldintermediate 382. This intermediate is converted to the substitutedhydrazine 383 by Cu(I)-catalyzed reaction with N-BOC hydrazine.

Scheme 68 illustrates the synthesis of compounds wherein Q is Q-44,G=CH₂. Nitroacid 384 (readily available by anyone with normal skills inthe art) is reacted with thiomorpholine sulphone to yield amide 385,which upon reduction to the amine and conversion of the nitro groupunder standard conditions results in hydrazine 386. This hydrazine canbe converted into compounds of formula I.B using the methods previouslyoutlined in Schemes 35 and 36.

Scheme 69 illustrates the synthesis of compounds wherein Q is Q-46.Piperadine derivative 387 is alkylated with protected bromohydrine.Removal of the alcohol protecting group yields intermediate 388, whichcan be oxidized to aldehyde 389. When G=NH, iodoaniline 390 is reactedwith 389 under reductive amination conditions, preferably sodiumtriacetoxyborohydride, to afford intermediate 391. This intermediate isconverted to the substituted hydrazine 392 by Cu(I)-catalyzed reactionwith N-BOC hydrazine. When G=O, iodophenol 393 is either alkylated with396 or reacted under Mitsunobu conditions with alcohol 388 to yieldintermediate 394. This intermediate is converted to the substitutedhydrazine 395 by Cu(I)-catalyzed reaction with N-BOC hydrazine.

Scheme 70 illustrates the synthesis of compounds wherein Q is Q-44,G=CH₂. Nitroacid 397 (readily available by anyone with normal skills inthe art) is reacted with thiomorpholine sulphone to yield amide 398,which upon reduction to the amine and conversion of the nitro groupunder standard conditions results in hydrazine 399. This hydrazine canbe converted into compounds of formula I.B using the methods previouslyoutlined in Schemes 35 and 36.

Affinity and Biological Assessment of p38-Alpha Kinase Inhibitors

A fluorescence binding assay is used to detect binding of inhibitors ofFormula I with unphosphorylated p38-alpha kinase as previouslydescribed: see J. Regan et al, Journal of Medicinal Chemistry (2002)45:2994.

1. p38 MAP Kinase Binding Assay

The binding affinities of small molecule modulators for p38 MAP kinasewere determined using a competition assay with SKF 86002 as afluorescent probe, modified based on published methods (C. Pargellis, etal Nature Structural Biology (2002) 9, 268-272. J. Regan, et al J. Med.Chem. (2002) 45, 2994-3008). Briefly, SKF 86002, a potent inhibitor ofp38 kinase (K_(d)=180 nM), displays an emission fluorescence around 420nm when excitated at 340 nm upon its binding to the kinase. Thus, thebinding affinity of an inhibitor for p38 kinase can be measured by itsability to decrease the fluorescence from SKF 86002. The assay wasperformed in a 384 plate (Greiner Nuclear 384 plate) on a PolarstarOptima plate reader (BMG). Typically, the reaction mixture contained 1μM SKF 86002, 80 nM p38 kinase and various concentrations of aninhibitor in 20 mM Bis-Tris Propane buffer, pH 7, containing 0.15% (w/v)n-octylglucoside and 2 mM EDTA in a final volume of 65 μl. The reactionwas initiated by addition of the enzyme. The plate was incubated at roomtemperature (˜25° C.) for 2 hours before reading at emission of 420 nmand excitation at 340 nm. By comparison of rfu (relative fluorescenceunit) values with that of a control (in the absence of an inhibitor),the percentage of inhibition at each concentration of the inhibitor wascalculated. IC₅₀ value for the inhibitor was calculated from the %inhibition values obtained at a range of concentrations of the inhibitorusing Prism. When time-dependent inhibition was assessed, the plate wasread at multiple reaction times such as 0.5, 1, 2, 3, 4 and 6 hours. TheIC₅₀ values were calculated at the each time point. An inhibition wasassigned as time-dependent if the IC₅₀ values decrease with the reactiontime (more than two-fold in four hours). This is illustrated below inTable 1.

TABLE 1 Example # IC50, nM Time-dependent 1 292 Yes 2 997 No 2 317 No 3231 Yes 4 57 Yes 5 1107 No 6 238 Yes 7 80 Yes 8 66 Yes 9 859 No 10 2800No 11 2153 No 12 ~10000 No 13 384 Yes 15 949 No 19 ~10000 No 21 48 Yes22 666 No 25 151 Yes 26 68 Yes 29 45 Yes 30 87 Yes 31 50 Yes 32 113 Yes37 497 No 38 508 No 41 75 Yes 42 373 No 43 642 No 45 1855 No 46 1741 No47 2458 No 48 3300 No 57 239 Yes IC50 values obtained at 2 hoursreaction timep-38 Alpha Kinase Assay (Spectrophometric Assay)

Activity of phosphorylated p-38 kinase was determined by following theproduction of ADP from the kinase reaction through coupling with thepyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al.Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH wascontinuously measured spectrophometrically. The reaction mixture (100μl) contained phospho p-38 alpha kinase (3.3 nM. Panvera), peptidesubstrate (IPTSPITTTYFFFKKK-OH, 0.2 mM), ATP (0.3 mM), MgCl₂ (10 mM),pyruvate kinase (8 units. Sigma), lactate dehydrogenase (13 units.Sigma), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 65 mM Trisbuffer, pH 7.5, containing 3.5% DMSO and 150 uMn-Dodecyl-B-D-maltopyranoside. The reaction was initiated by adding ATP.The absorption at 340 nm was monitored continuously for up to 4 hours at30° C. on Polarstar Optima plate reader (BMG). The kinase activity(reaction rate) was calculated from the slope at the time frame from 1.5h to 2 h. Under these conditions, a turn over number (k_(cat)) of ˜1 s⁻¹was obtained. The reaction rates calculated from different time framessuch as 0.5 min to 0.5 h, 0.5 h to 1 h, 1.5 h to 2 h or 2.5 h to 3 hwere generally constant.

For inhibition determinations, test compounds were incubated with thereaction mixture for ˜5 min before adding ATP to start the reaction.Percentage of inhibition was obtained by comparison of reaction ratewith that of a control well containing no test compound. IC₅₀ valueswere calculated from a series of % inhibition values determined at arange of concentrations of each inhibitor using Prism to process thedata and fit inhibition curves. Generally, the rates obtained at thetime frame of 1.5 h to 2 h were used for these calculations. Inassessing whether inhibition of a test compound was time-dependent(i.e., greater inhibition with a longer incubation time), the values of% inhibition and/or IC50 values obtained from other time frames werealso calculated for the inhibitor. The biological activity for compoundsof the present invention in the spectrophotometric assay are illustratedin Tables 2 and 3.

TABLE 2 Example # IC50, uM % inhibition @ concentration, uM 1 0.067 20.29 3 0.019 4 0.609 5 0.514 6 0.155 7 0.165 9 0.355 10 83% @ 10 110.953 12 70% @ 10 13 0.269 14 0.096 15 0.53 17 40% @ 10 18 60% @ 10 210.171 22 0.445 25 0.055 26 0.19 29 0.011 30 0.251 31 0.056 32 0.307 380.51 39 0.012 40 0.055 41 0.013 42 0.425 43 7.5 45 0.48 46 1 47 0.295 482 49 0.071 51 0.033 52 0.416 53 0.109 54  68% @ 1.0 55 0.74 57 0.782 580.172 59 0.709 60 0.264 D 0.179 F 0.437

TABLE 3 Example # IC50, uM % Inhibition @ concentration, uM 145 1.3 146 9% @ 10 147 27% @ 10 150 53% @ 10 154 21% @ 10 155 58% @ 10 160 0.044161 0.1 162 0.65 163 0.464 196 0.028 197 0.243 198 0.137 199 0.684 200 73% @ 1.0 201 0.029 202 1.9 203 0.328 204 0.008 206 0.013 207 0.033 2090.354 234 11 284 1.95 285 0.102 286 0.079 287 0.041 288 0.104 289 1.3291 5.1 294 2.1 295 1.2 296 0.284 297 0.34 298 0.025 299 2.3 300 0.251301 0.63 302 0.077

Human Peripheral Blood Mononuclear Leukocyte Cell Assay.

Human peripheral blood mononuclear leukocytes are challenged with 25ng/mL lipopolysaccharide (LPS) in the absence or presence of TestCompound and incubated for 16 hours as described by Welker P. et al,International Archives Allergy and Immunology (1996) 109: 110. Thequantity of LPS-induced tumor necrosis factor-alpha (TNF-alpha) cytokinerelease is measured by a commercially available Enzyme-LinkedImmunosorbent Assay (ELISA) kit. Test compounds are evaluated for theirability to inhibit TNF-alpha release. Table 2 records IC₅₀ values forinhibition of TNF-alpha release by Test Compounds of the presentinvention, wherein the IC₅₀ value, in micromolar concentration,represents the concentration of Test Compound resulting in a 50%inhibition of TNF-alpha release from human peripheral blood mononuclearleukocytes as compared to control experiments containing no TestCompound. Test compounds evaluated are illustrated in Table 4.

TABLE 4 Example Number IC50, uM 3 6.1 13 6.32 21 3.4 29 2.68 31 4.52 602.34 296 3.49 300 4.78 302 5.45

EXAMPLES

The following examples set forth preferred methods in accordance withthe invention. It is to be understood, however, that these examples areprovided by way of illustration and nothing therein should be taken as alimitation upon the overall scope of the invention.

[Boc-sulfamide]aminoester (Reagent AA),1,5,7,-trimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1]nonane-7-carboxylic acid(Reagent BB), and Kemp acid anhydride (Reagent CC) was preparedaccording to literature procedures. See Askew et. al J. Am. Chem. Soc.1989, 111, 1082 for further details.

Example A

To a solution (200 mL) of m-amino benzoic acid (200 g, 1.46 mol) inconcentrated HCl was added an aqueous solution (250 mL) of NaNO₂ (102 g,1.46 mol) at 0° C. The reaction mixture was stirred for 1 h and asolution of SnCl₂.2H₂O (662 g, 2.92 mol) in concentrated HCl (2 L) wasthen added at 0° C., and the reaction stirred for an additional 2 h atRT. The precipitate was filtered and washed with ethanol and ether toyield 3-hydrazino-benzoic acid hydrochloride as a white solid.

The crude material from the previous reaction (200 g, 1.06 mol) and4,4-dimethyl-3-oxo-pentanenitrile (146 g, 1.167 mol) in ethanol (2 L)were heated to reflux overnight. The reaction solution was evaporated invacuo and the residue purified by column chromatography to yield ethyl3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)benzoate (Example A, 116 g, 40%)as a white solid together with3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoic acid (93 g, 36%). ¹H NMR(DMSO-d₆): 8.09 (s, 1H), 8.05 (brd, J=8.0 Hz, 1H), 7.87 (brd, J=8.0 Hz,1H), 7.71 (t, J=8.0 Hz, 1H), 5.64 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.34(t, J=7.2 Hz, 3H), 1.28 (s, 9H).

Example B

To a solution of 1-naphthyl isocyanate (9.42 g, 55.7 mmol) and pyridine(44 mL) in THF (100 mL) was added a solution of Example A (8.0 g, 27.9mmol) in ThIF (200 mL) at 0° C. The mixture was stirred at RT for 1 h,heated until all solids were dissolved, stirred at RT for an additional3 h and quenched with H₂O (200 mL). The precipitate was filtered, washedwith dilute HCl and H₂O, and dried in vacuo to yield ethyl3-[3-t-butyl-5-(3-naphthalen-1-yl)ureido)-1H-pyrazol-1-yl]benzoate (12.0g, 95%) as a white power. ¹H NMR (DMSO-d₆): 9.00 (s, 1H), 8.83 (s, 1H),8.25 7.42 (m, 11H), 6.42 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 1.26 (s, 9H),1.06 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 457.10 (M+H⁺).

Example C

To a solution of Example A (10.7 g, 70.0 mmol) in a mixture of pyridine(56 mL) and THF (30 mL) was added a solution of 4-nitrophenyl4-chlorophenylcarbamate (10 g, 34.8 mmol) in THF (150 mL) at 0° C. Themixture was stirred at RT for 1 h and heated until all solids weredissolved, and stirred at RT for an additional 3 h. H₂O (200 mL) andCH₂Cl₂ (200 mL) were added, the aqueous phase separated and extractedwith CH₂Cl₂ (2×100 mL). The combined organic layers were washed with 1NNaOH, and 0.1N HCl, saturated brine and dried over anhydrous Na₂SO₄. Thesolvent was removed in vacuo to yield ethyl3-{3-tert-butyl-5-[3-(4-chlorophenyl)ureido]-1H-pyrazol-1-yl}benzoate(8.0 g, 52%). ¹H NMR (DMSO-d₆): δ 9.11 (s, 1H), 8.47 (s, 1H), 8.06 (m,1H), 7.93 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.65 (dd, J=8.0,7.6 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 6.34 (s,1H), 4.30 (q, J=6.8 Hz, 2H), 1.27 (s, 9H), 1.25 (t, J=6.8 Hz, 3H); MS(ESI) m/z: 441 (M⁺+H).

Example D

To a stirred solution of Example B (8.20 g, 18.0 mmol) in THF (500 mL)was added LiAlH₄ powder (2.66 g, 70.0 mmol) at −10° C. under N₂. Themixture was stirred for 2 h at RT and excess LiAlH₄ destroyed by slowaddition of ice. The reaction mixture was acidified to pH=7 with diluteHCl, concentrated in vacuo and the residue extracted with EtOAc. Thecombined organic layers were concentrated in vacuo to yield1-{3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea(7.40 g, 99%) as a white powder. ¹H NMR (DMSO-d₆): 9.19 (s, 1H), 9.04(s, 1H), 8.80 (s, 1H), 8.26-7.35 (m, 11H), 6.41 (s, 1H), 4.60 (s, 2H),1.28 (s, 9H); MS (ESI) m/z: 415 (M+H⁺).

Example E

A solution of Example C (1.66 g, 4.0 mmol) and SOCl₂ (0.60 mL, 8.0 mmol)in CH₃Cl (100 mL) was refluxed for 3 h and concentrated in vacuo toyield1-{3-tert-butyl-1-[3-chloromethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea(1.68 g, 97%) was obtained as white powder. ¹H NMR (DMSO-d₆): δ 9.26 (s,1H), 9.15 (s, 1H), 8.42-7.41 (m, 11H), 6.40 (s, 1H), 4.85 (s, 2H), 1.28(s, 9H). MS (ESI) m/z: 433 (M+H⁺).

Example F

To a stirred solution of Example C (1.60 g, 3.63 mmol) in THF (200 mL)was added LiAlH₄ powder (413 mg, 10.9 mmol) at −10° C. under N₂. Themixture was stirred for 2 h and excess LiAlH₄ was quenched by addingice. The solution was acidified to pH=7 with dilute HCl. Solvents wereslowly removed and the solid was filtered and washed with EtOAc (200+100mL). The filtrate was concentrated to yield1-{3-tert-butyl-1-[3-hydroxymethyl)phenyl]-1H-pyrazol-5-yl)}-3-(4-chlorophenyl)urea(1.40 g, 97%). ¹H NMR (DMSO-d₆): δ 9.11 (s, 1H), 8.47 (s, 1H), 7.47-7.27(m, 8H), 6.35 (s, 1H), 5.30 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H),1.26 (s, 9H); MS (ESI) m/z: 399 (M+H⁺).

Example G

A solution of Example F (800 mg, 2.0 mmol) and SOCl₂ (0.30 mL, 4 mmol)in CHCl₃ (30 mL) was refluxed gently for 3 h. The solvent was evaporatedin vacuo and the residue was taken up to in CH₂Cl₂ (2×20 mL). Afterremoval of the solvent,1-{3-tert-butyl-1-[3-(chloromethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea(812 mg, 97%) was obtained as white powder. ¹H NMR (DMSO-d₆): δ 9.57 (s,1H), 8.75 (s, 1H), 7.63 (s, 1H), 7.50-7.26 (m, 7H), 6.35 (s, 1H), 4.83(s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 417 (M+H⁺).

Example H

To a suspension of LiAlH₄ (5.28 g, 139.2 mmol) in THF (1000 mL) wasadded Example A (20.0 g, 69.6 mmol) in portions at 0° C. under N₂. Thereaction mixture was stirred for 5 h, quenched with 1 N HCl at 0° C. andthe precipitate was filtered, washed by EtOAc and the filtrateevaporated to yield[3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl]methanol (15.2 g, 89%).¹H NMR (DMSO-d₆): 7.49 (s, 1H), 7.37 (m, 2H), 7.19 (d, J=7.2 Hz, 1H),5.35 (s, 1H), 5.25 (t, J=5.6 Hz, 1H), 5.14 (s, 2H), 4.53 (d, J=5.6 Hz,2H), 1.19 (s, 9H); MS (ESI) m/z: 246.19 (M+H⁺).

The crude material from the previous reaction (5.0 g, 20.4 mmol) wasdissolved in dry THF (50 mL) and SOCl₂ (4.85 g, 40.8 mmol), stirred for2 h at RT, concentrated in vacuo to yield3-tert-butyl-1-(3-chloromethylphenyl)-1H-pyrazol-5-amine (5.4 g), whichwas added to N₃ (3.93 g, 60.5 mmol) in DMF (50 mL). The reaction mixturewas heated at 30° C. for 2 h, poured into H₂O (50 mL), and extractedwith CH₂Cl₂. The organic layers were combined, dried over MgSO₄, andconcentrated in vacuo to yield crude3-tert-butyl-1-[3-(azidomethyl)phenyl]-1H-pyrazol-5-amine (1.50 g, 5.55mmol).

Example I

Example H was dissolved in dry THF (10 mL) and added a THF solution (10mL) of 1-isocyano naphthalene (1.13 g, 6.66 mmol) and pyridine (5.27 g,66.6 mmol) at RT. The reaction mixture was stirred for 3 h, quenchedwith H₂O (30 mL), the resulting precipitate filtered and washed with 1NHCl and ether to yield1-[2-(3-azidomethyl-phenyl)-5-t-butyl-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea(2.4 g, 98%) as a white solid.

The crude material from the previous reaction and Pd/C (0.4 g) in THF(30 mL) was hydrogenated under 1 atm at RT for 2 h. The catalyst wasremoved by filtration and the filtrate concentrated in vacuo to yield1-{3-tert-butyl-1-[3-(amonomethyl)phenyl}-1H-pyrazol-5-yl)-3-(naphthalene-1-yl)urea(2.2 g, 96%) as a yellow solid. ¹HNMR (DMSO-d₆): 9.02 (s, 1H), 7.91 (d,J=7.2 Hz, 1H), 7.89 (d, J=7.6 Hz, 2H), 7.67-7.33 (m, 9H), 6.40 (s, 1H),3.81 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 414 (M+H⁺).

Example J

To a solution of Example H (1.50 g, 5.55 mmol) in dry THF (10 mL) wasadded a THF solution (10 mL) of 4-chlorophenyl isocyanate (1.02 g, 6.66mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture wasstirred for 3 h and then H₂O (30 mL) was added. The precipitate wasfiltered and washed with 1N HCl and ether to give1-{3-tert-butyl-1-[3-(amonomethyl)phenyl}-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea(2.28 g, 97%) as a white solid, which was used for next step withoutfurther purification. MS (ESI) m/z: 424 (M+H⁺).

Example K

To a solution of benzyl amine (16.5 g, 154 mmol) and ethyl bromoacetate(51.5 g, 308 mmol) in ethanol (500 mL) was added K₂CO₃ (127.5 g, 924mmol). The mixture was stirred at RT for 3 h, was filtered, washed withEtOH, concentrated in vacuo and chromatographed to yieldN-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethyl ester (29 g,67%). ¹H NMR (CDCl₃): δ 7.39-7.23 (m, 5H), 4.16 (q, J=7.2 Hz, 4H), 3.91(s, 2H), 3.54 (s, 4H), 1.26 (t, J=7.2 Hz, 6H); MS (ESI): m/e: 280(M⁺+H).

A solution of N-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethylester (7.70 g, 27.6 mmol) in methylamine alcohol solution (25-30%, 50mL) was heated to 50° C. in a sealed tube for 3 h, cooled to RT andconcentrated in vacuo to yieldN-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide inquantitative yield (7.63 g). ¹H NMR (CDCl₃): δ 7.35-7.28 (m, 5H), 6.75(br s, 2H), 3.71 (s, 2H); 3.20 (s, 4H), 2.81 (d, J=5.6 Hz, 6H); MS (ESI)m/e 250(M+H⁺).

The mixture of N-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycinemethylamide (3.09 g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd/C (0.15g). The mixture was stirred and heated to 40° C. under 40 psi H₂ for 10h, filtered and concentrated in vacuo to yieldN-(2-methylamino-2-oxoethyl)-glycine methylamide in quantitative yield(1.76 g). ¹H NMR (CDCl₃): δ 6.95 (br s, 2H), 3.23 (s, 4H), 2.79 (d,J=6.0, 4.8 Hz), 2.25 (br s 1H); MS (ESI) m/e 160 (M+H⁺)

Example 1

To a solution of 1-methyl-[1,2,4]triazolidine-3,5-dione (188 mg, 16.4mmol) and sodium hydride (20 mg, 0.52 mmol) in DMSO (1 mL) was addedExample E (86 mg, 0.2 mmol). The reaction was stirred at RT overnight,quenched with H₂O (10 mL), extracted with CH₂Cl₂, and the organic layerwas separated, washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by preparative HPLC to yield1-(3-tert-butyl-1-{3-[(1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-(naphthalene-1-yl)urea(Example 1, 14 mg). ¹H NMR (CD₃OD): δ7.88-7.86 (m, 2H), 7.71-7.68 (m,2H), 7.58 (m, 2H), 7.60-7.42 (m, 5H), 6.49 (s, 1H), 4.85 (s, 1H), 1.34(s, 9H), 1.27 (s, 6H); MS (ESI) m/z: 525 (M+H⁺).

Example 2

The title compound was synthesized in a manner analogous to Example 1,utilizing Example G to yield1-(3-tert-butyl-1-{3-[(1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea¹H NMR (CD₃OD): δ 7.2-7.5˜(m, 7H), 6.40 (s 1H), 4.70 (s, 2H), 2.60 (d,J=14 Hz, 2H), 1.90 (m, 1H), 1.50 (m, 1H), 1.45 (s, 9H), 1.30 (m, 2H),1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 (M+H⁺).

Example 3

A mixture of compound 1,1-Dioxo-[1,2,5]thiadiazolidin-3-one (94 mg, 0.69mmol) and NaH (5.5 mg, 0.23 mmol) in THF (2 mL) was stirred at −10° C.under N₂ for 1 h until all NaH was dissolved. Example E (100 mg, 0.23mmol) was added and the reaction was allowed to stir at RT overnight,quenched with H₂O, and extracted with CH₂Cl₂. The combined organiclayers were concentrated in vacuo and the residue was purified bypreparative HPLC to yield1-(3-tert-butyl-1-{[3-(1,1,3-trioxo-[1,2,5]thiadiazolidin-2-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-naphthalen-1-yl)urea(18 mg) as a white powder. ¹H NMR (CD₃OD): δ 7.71-7.44 (m, 11H), 6.45(s, 1H), 4.83 (s, 2H), 4.00 (s, 2H), 1.30 (s, 9H). MS (ESI) m/z: 533.40(M+H⁺).

Example 4

The title compound was obtained in a manner analogous to Example 3utilizing Example G. to yield1-(3-tert-butyl-1-{[3-(1,1,3-trioxo-[1,2,5]thiadiazolidin-2-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.¹H NMR (CD₃OD): δ 7.38-7.24 (m, 8H), 6.42 (s, 1H), 4.83 (s, 2H), 4.02(s, 2H), 1.34 (s, 9H); MS (ESI) m/z: 517 (M+H⁺).

Example 5

To a stirred solution of chlorosulfonyl isocyanate (19.8 L, 0.227 mmol)in CH₂Cl₂ (0.5 mL) at 0° C. was added pyrrolidine (18.8 μL, 0.227 mmol)at such a rate that the reaction solution temperature did not rise above5° C. After stirring for 1.5 h, a solution of Example J (97.3 mg, 0.25mmol) and Et₃N (95 μL, 0.678 mmol) in CH₂Cl₂ (1.5 mL) was added at sucha rate that the reaction temperature didn't rise above 5° C. When theaddition was completed, the reaction solution was warmed to RT andstirred overnight. The reaction mixture was poured into 10% HCl,extracted with CH₂Cl₂, the organic layer washed with saturated NaCl,dried over MgSO₄, and filtered. After removal of the solvents, the crudeproduct was purified by preparative HPLC to yield1-(3-tert-butyl-1-[[3-N-[[(1-pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]phenyl]-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.¹H NMR (CD₃OD): δ 7.61 (s, 1H), 7.43-7.47 (m, 3H), 7.23-7.25 (dd, J=6.8Hz, 2H), 7.44 (dd, J=6.8 Hz, 2H), 6.52 (s, 1H), 4.05 (s, 2H), 3.02 (m,4H), 1.75 (m, 4 H), 1.34 (s, 9H); MS (ESI) m/z: 574.00 (M+H⁺).

Example 6

The title compound was made in a manner analogous to Example 5 utilizingExample I to yield1-(3-tert-butyl-1-[[3-N-[[(1-pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]-phenyl]-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.¹HNMR (CDCl₃): δ 7.88 (m, 2H), 7.02-7.39 (m, 2H), 7.43-7.50 (m, 7H),6.48 (s, 1H), 4.45 (s, 1H), 3.32-3.36 (m, 4H), 1.77-1.81 (m, 4H), 1.34(s, 9H); MS (ESI) m/z: 590.03 (M+H⁺).

Example 7

To a stirred solution of chlorosulfonyl isocyanate (19.8 μΛ, 0.227 μμoλ)ιν XH₁Xλ₁ (0.5 μΛ) ατ 0° C., was added Example J (97.3 mg, 0.25 mmol) atsuch a rate that the reaction solution temperature did not rise above 5°C. After being stirred for 1.5 h, a solution of pyrrolidine (18.8 μL,0.227 mmol) and Et₃N (95 μL, 0.678 mmol) in CH₂Cl₂ (1.5 mL) was added atsuch a rate that the reaction temperature didn't rise above 5° C. Whenaddition was completed, the reaction solution was warmed to RT andstirred overnight. The reaction mixture was poured into 10% HCl,extracted with CH₂Cl₂, the organic layer was washed with saturated NaCl,dried over Mg₂SO₄, and filtered. After removal of the solvents, thecrude product was purified by preparative HPLC to yield1-(3-tert-butyl-1-[[3-N-[[(1-pyrrolidinylsulphonyl)amino]carbonyl]aminomethyl]phenyl]-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.¹HNMR (CDCl₃): δ 7.38 (m, 1H), 7.36-7.42 (m, 3H), 7.23 (d, J=8.8 Hz,2H), 7.40 (d, J=8.8 Hz, 2H), 6.43 (s, 1H), 4.59 (s, 1H), 4.43 (s, 2H),1.81 (s, 2H), 1.33 (s, 9H); MS (ESI) m/z: 574.10 (M+H⁺).

Example 8

The title compound was made in a manner analogous to Example 7 utilizingExample I to yield1-(3-tert-butyl-1-[[3-N-[[(1-pyrrolidinylsulphonyl)amino]carbonyl]aminomethyl]-phenyl]-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.¹HNMR (CDCl₃): δ 7.88 (m, 2H), 7.02-7.39 (m, 2H), 7.43-7.50 (m, 7H),6.48 (s, 1H), 4.45 (s, 1H), 3.32-3.36 (m, 4H), 1.77-1.81 (m, 4H), 1.34(s, 9H); MS (ESI) m/z: 590.03 (M+H⁺).

Example 9

To a solution of Reagent BB (36 mg, 0.15 mmol), Example I (62 mg, 0.15mmol), HOBt (40 mg, 0.4 mmol) and NMM (0.1 mL, 0.9 mmol) in DMF (10 mL)was added EDCI (58 mg, 0.3 mmol). After being stirred overnight, themixture was poured into water (15 mL) and extracted with EtOAc (35 mL).The organic layers were combined, washed with brine, dried with Na₂SO₄,and concentrated in vacuo. The residue was purified by preparative TICto yield1,5,7-trimethyl-2,4-dioxo-3-azabicyclo[3.3.1]nonane-7-carboxylic acid3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]benzylamide (22mg). ¹H NMR (CDCl₃): δ 8.40 (s, 1H), 8.14 (d, J=8.0 Hz, 2H), 7.91 (s,1H), 7.87 (s, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.73(d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.57-7.40 (m, 4H), 7.34 (d,J=7.6 Hz, 1H), 6.69 (s, 1H), 6.32 (t, J=5.6 Hz, 1H), 5.92 (brs, 1H),4.31 (d, J=5.6 Hz, 2H), 2.37 (d, J=14.8 Hz, 2H), 1.80 (d, J=13.2 Hz,1H), 1.35 (s, 9H), 1.21 (d, J=13.2 Hz, 1H), 1.15 (s, 3H), 1.12 (d,J=12.8 Hz, 2H), 1.04 (s, 6H); MS (ESI) m/z: 635 (M+H⁺).

Example 10

The title compound, was synthesized in a manner analogous to Example 9utilizing Example J to yield1,5,7-trimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1]nonane-7-carboxylic acid3-{3-t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyrazol-1-yl}benzylamide. ¹HNMR (CDCl₃): δ 8.48 (s, 1H), 7.78 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.69(s, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.26 (m, 3H),6.62 (s, 1H), 6.35 (t, J=6.0 Hz, 1H), 5.69 (brs, 1H), 4.26 (d, J=6.0 Hz,2H), 2.48 (d, J=14.0 Hz, 2H), 1.87 (d, J=13.6 Hz, 1H), 1.35 (s, 9H),1.25 (m, 6H), 1.15 (s, 6H); MS (ESI) m/z: 619 (M+H⁺).

Example 11

A mixture of Example I (41 mg, 0.1 mmol), Kemp acid anhydride (24 mg,0.1 mmol) and Et₃N (100 mg, 1 mmol) in anhydrous CH₂Cl₂ (2 mL) werestirred overnight at RT, and concentrated in vacuo. Anhydrous benzene(20 mL) was added to the residue, the mixture was refluxed for 3 h,concentrated in vacuo and purified by preparative HPLC to yield3-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]-benzyl}-1,5-di-methyl-2,4-dioxo-3-aza-bicyclo[3.3.1]nonane-7-carboxylicacid (8.8 mg, 14%). ¹H NMR (CD₃OD): δ 7.3-7.4 (m, 2H), 7.20 (m, 2H),7.4-7.6 (m, 7H), 6.50 (m, 1H), 4.80 (s, 2H), 2.60 (d, J=14 Hz, 2H), 1.90(m, 1H), 1.40 (m, 1H), 1.30 (m, 2H), 1.20 (s, 3H), 1.15 (s, 6H); MS(ESI) m/z: 636 (M+H⁺).

Example 12

The title compound, was synthesized in a manner analogous to Example 11utilizing Example J to yield3-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]-benzyl}-1,5-dimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1]nonane-7-carboxylicacid. ¹H NMR (CD₃OD): δ 7.2-7.5 (m, 7H), 6.40 (s 1H), 4.70 (s, 2H), 2.60(d, J=14 Hz, 2H), 1.90 (m, 1H), 1.50 (m, 1H), 1.45 (s, 9H), 1.30 (m,2H), 1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 (M+H⁺).

Example 13

The title compound was synthesized in a manner analogous to Example 1utilizing Example E and 4,4-dimethyl-3,5-dioxo-pyrazolidine to yield1-(3-tert-butyl-1-{3-[(4,4-dimethyl-3,5-dioxopyrazolidin-1-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.¹H NMR (CD₃OD): δ 7.88-7.86 (m, 2H), 7.71-7.68 (m, 2H), 7.58 (m, 2H),7.60-7.42 (m, 5H), 6.49 (s, 1H), 4.85 (s, 1H), 1.34 (s, 9H), 1.27 (s,6H); MS (ESI) m/z: 525 (M+H⁺).

Example 14

The title compound was synthesized in a manner analogous to Example 1utilizing Example G and 4,4-dimethyl-3,5-dioxo-pyrazolidine to yield1-(3-tert-butyl-1-{3-[(4,4-dimethyl-3,5-dioxopyrazolidin-1-yl)methyl]phenyl}-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.¹H NMR (CD₃OD): δ 7.60-7.20 (m, 8H), 6.43 (s, 1H), 4.70 (s, 1H), 1.34(s, 9H), 1.26 (s, 6H); MS (ESI) m/z: 509, 511 (M+H⁺).

Example 15

Example B was saponified with 2N LiOH in MeOH, and to the resulting acid(64.2 mg, 0.15 mmol) were added HOBt (30 mg, 0.225 mmol), Example K (24mg, 0.15 mmol) and 4-methylmorpholine (60 mg, 0.60 mmol 4.0 equiv), DMF(3 mL) and EDCI (43 mg, 0.225 mmol). The reaction mixture was stirred atRT overnight and poured into H₂O (3 mL), and a white precipitatecollected and further purified by preparative HPLC to yield1-[1-(3-{bis[(methylcarbamoyl)methyl]carbamoyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-3-(naphthalen-1-yl)urea(40 mg). ¹H NMR (CDCl₃): δ 8.45 (brs, 1H), 8.10 (d, J=7.6 Hz, 1H),7.86-7.80 (m, 2H), 7.63-7.56 (m, 2H), 7.52 (s, 1H), 7.47-7.38 (m, 3H),7.36-7.34 (m, 1H), 7.26 (s, 1H), 7.19-7.17 (m, 2H), 6.60 (s, 1H), 3.98(s, 2H), 3.81 (s, 3H), 2.87 (s, 3H), 2.63 (s, 3H), 1.34 (s, 9H); MS(ESI) m/z: 570 (M+H⁺).

Example 16

The title compound was synthesized in a manner analogous to Example 15utilizing Example C (37 mg) and Example K to yield1-[1-(3-{bis[(methylcarbamoyl)methyl]carbamoyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-3-(4-chlorophenyl)urea.¹H NMR (CD₃OD): δ 8.58 (brs, 1H), 8.39 (brs, 1H), 7.64-7.62 (m, 3H),7.53-7.51 (m, 1H), 7.38 (d, J=9.2 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 6.44(s, 1H), 4.17 (s, 2H), 4.11 (s, 2H), 2.79 (s, 3H), 2.69 (s, 3H),1.34-1.28 (m, 12H); MS (ESI) m/z: 554 (M+H⁺).

Example 17

Example B was saponified with 2N LiOH in MeOH, and to the resulting acid(0.642 g, 1.5 mmol) in dry THF (25 mL) at −78° C. were added freshlydistilled triethylamine (0.202 g, 2.0 mmol) and pivaloyl chloride (0.216g, 1.80 mmol) with vigorous stirring. After stirring at −78° C. for 15min and at 0° C. for 45 min, the mixture was again cooled to −78° C. andthen transferred into the THF solution of lithium salt ofD-4-phenyl-oxazolidin-2-one [*: The lithium salt of the oxazolidinoneregeant was previously prepared by the slow addition of n-BuLi (2.50M inhexane, 1.20 mL, 3.0 mmol) into THF solution ofD-4-phenyl-oxazoldin-2-one at −78° C.]. The reaction solution wasstirred at −78° C. for 2 h and RT overnight, and then quenched with aq.ammonium chloride and extracted with dichloromethane (100 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated in vacuo.The residue was purified by preparative HPLC to yieldD-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(naphthalen-1-yl)urea(207 mg, 24%). ¹H NMR (CDCl₃): δ 8.14-8.09 (m, 2H), 8.06 (s, 1H),7.86-7.81 (m, 4H), 7.79 (s, 1H), 7.68-7.61 (m, 2H), 7.51-7.40 (m, 9H),6.75 (s, 1H), 5.80 (t, J=9.2, 7.6 Hz, 1H), 4.89 (t, J=9.2 Hz, 1H), 4.42(dd, J=9.2, 7.6 Hz, 1H), 1.37 (s, 9H); MS (ESI) m/z: 574 (M+H⁺).

Example 18

The title compound was synthesized in a manner analogous to Example 17utilizing Example B and L-4-phenyl-oxazolidin-2-one to yieldL-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(naphthalen-1-yl)urea¹H NMR (CDCl₃): δ 8.14-8.09 (m, 2H), 8.06 (s, 1H), 7.86-7.81 (m, 4H),7.79 (s, 1H), 7.68-7.61 (m, 2H), 7.51-7.40 (m, 9H), 6.75 (s, 1H), 5.80(t, J=9.2, 7.6 Hz, 1H), 4.89 (t, J=9.2 Hz, 1H), 4.42 (dd, J=9.2, 7.6 Hz,1H), 1.37 (s, 9H); MS (ESI) m/z: 574 (M+H⁺)

Example 19

The title compound was synthesized in a manner analogous to Example 17utilizing Example C and D-4-phenyl-oxazolidin-2-one to yieldD-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(4-chlorophenyl)urea.¹H NMR (CDCl₃): δ 7.91 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.79 (d, J=7.6Hz, 1H), 7.71 (m, 1H), 7.65 (m, 1H), 7.49-7.40 (m, 8H), 7.26-7.24 (m,2H), 6.68 (s, 1H), 5.77 (dd, J=8.8, 8.0 Hz, 1H), 4.96 (t, 8.8 Hz, 1H),4.44 (dd, J=8.8, 8.0 Hz, 1H), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+H⁺)

Example 20

The title compound was synthesized in a manner analogous to Example 17utilizing Example C and L-4-phenyl-oxazolidin-2-one to yieldL-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(4-chlorophenyl)urea.¹H NMR (CDCl₃): δ 7.91 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.79 (d, J=7.6Hz, 1H), 7.71 (m, 1H), 7.65 (m, 1H), 7.49-7.40 (m, 8H), 7.26-7.24 (m,2H), 6.68 (s, 1H), 5.77 (dd, J=8.8, 8.0 Hz, 1H), 4.96 (t, 8.8 Hz, 1H),4.44 (dd, J=8.8, 8.0 Hz, 1H), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+H⁺)

Example L

To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH₂Cl₂(40 ml, with a catalytic amount of DMF) at 0° C. under N₂ was addedoxalyl chloride (1.1 ml) drop wise. The reaction mixture was stirred for40 min morpholine (2.5 g) was added. After stirring for 20 min, thereaction mixture was filtered. The filtrate was concentrated in vacuo toyield 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone as a solid (2 g). Amixture of 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone (2 g) and 10% Pdon activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30psi for 3 h and filtered over Celite. Removal of the volatiles in vacuoprovided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). Asolution of 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7mmol) was dissolved in 6 N HCl (15 ml), cooled to 0° C., and vigorouslystirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added.The reaction mixture was stirred at 0° C. for 3 h. The pH was adjustedto pH 14 with solid potassium hydroxide and extracted with EtOAc. Thecombined organic extracts were concentrated in vacuo provided2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g).2-(3-Hydrazinophenyl)-1-morpholin-4-yl-ethanone (3 g) and4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and6 N HCl (1 ml) were refluxed for 1 h and cooled to RT. The reactionmixture was neutralized by adding solid sodium hydrogen carbonate. Theslurry was filtered and removal of the volatiles in vacuo provided aresidue that was extracted with ethyl acetate. The volatiles wereremoved in vacuo to provide2-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]-1-morpholinoethanone(4 g), which was used without further purification.

Example 21

A mixture of Example L (0.2 g, 0.58 mmol) and 1-naphthylisocyanate (0.10g, 0.6 mmol) in dry CH₂Cl₂ (4 ml) was stirred at RT under N₂ for 18 h.The solvent was removed in vacuo and the crude product was purified bycolumn chromatography using ethyl acetate/hexane/CH₂Cl₂ (3/1/0.7) as theeluent (0.11 g, off-white solid) to yield1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalene-1-yl)urea.mp: 194-196; ¹H NMR (200 MHz, DMSO-d₆): δ 9.07 (1H, s), 8.45 (s, 1H),8.06-7.93 (m, 3H), 7.69-7.44 (m, 7H), 7.33-7.29 (d, 6.9 Hz, 1H), 6.44(s, 1H), 3.85 (m, 2H), 3.54-3.45 (m, 8H), 1.31 (s, 9H); MS:

Example 22

The title compound was synthesized in a manner analogous to Example 21utilizing Example L (0.2 g, 0.58 mmol) and 4-chlorophenylisocyanate(0.09 g, 0.6 mmol) to yield1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea.mp: 100 104; ¹H NMR (200 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.45 (s, 1H),7.52-7.30 (m, 8H), 6.38 (s, 1H), 3.83 (m, 1H), 3.53-3.46 (m, 8H), 1.30(s, 9H); MS:

Example 23

The title compound is synthesized in a manner analogous to Example 21utilizing Example L (0.2 g, 0.58 mmol) and phenylisocyanate (0.09 g, 0.6mmol) to yield1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-phenylurea.

Example 24

The title compound is synthesized in a manner analogous to Example 21utilizing Example L (0.2 g, 0.58 mmol) and1-isocyanato-4-methoxy-naphthalene to yield1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-(1-methoxynaphthalen-4-yl)urea.

Example M

The title compound is synthesized in a manner analogous to Example Cutilizing Example A and phenylisocyanate to yield ethyl3-(3-tert-butyl-5-(3-phenylureido)-1H-pyrazol-1-yl)benzoate.

Example N

A solution of (3-nitrophenyl)acetic acid (23 g, 127 mmol) in methanol(250 ml) and a catalytic amount of concentrated in vacuo H₂SO₄ washeated to reflux for 18 h. The reaction mixture was concentrated invacuo to a yellow oil. This was dissolved in methanol (250 ml) andstirred for 18 h in an ice bath, whereupon a slow flow of ammonia wascharged into the solution. The volatiles were removed in vacuo. Theresidue was washed with diethyl ether and dried to afford2-(3-nitrophenyl)acetamide (14 g, off-white solid). ¹H NMR (CDCl₃): δ8.1 (s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 7.5 (m, 1H), 7.1 (bd s, 1H), 6.2(brs, 1H), 3.6 (s, 2H).

The crude material from the previous reaction (8 g) and 10% Pd onactivated carbon (1 g) in ethanol (100 ml) was hydrogenated at 30 psifor 18 h and filtered over Celite. Removal of the volatiles in vacuoprovided 2-(3-aminophenyl)acetamide (5.7 g). A solution of this material(7 g, 46.7 mmol) was dissolved in 6 N HCl (100 ml), cooled to 0° C., andvigorously stirred. Sodium nitrite (3.22 g, 46.7 mmol) in water (50 ml)was added. After 30 min, tin (II) chloride dihydrate (26 g) in 6 N HCl(100 ml) was added. The reaction mixture was stirred at 0° C. for 3 h.The pH was adjusted to pH 14 with 50% aqueous NaOH solution andextracted with ethyl acetate. The combined organic extracts wereconcentrated in vacuo provided 2-(3-hydrazinophenyl)acetamide.

The crude material from the previous reaction (ca. 15 mmol) and4,4-dimethyl-3-oxopentanenitrile (1.85 g, 15 mmol) in ethanol (60 ml)and 6 N HCl (1.5 ml) was refluxed for 1 h and cooled to RT. The reactionmixture was neutralized by adding solid sodium hydrogen carbonate. Theslurry was filtered and removal of the volatiles in vacuo provided aresidue, which was extracted with ethyl acetate. The solvent was removedin vacuo to provide2-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]acetamide as a whitesolid (3.2 g), which was used without further purification.

Example 25

A mixture of Example N (2 g, 0.73 mmol) and 1-naphthylisocyanate (0.124g, 0.73 mmol) in dry CH₂Cl₂ (4 ml) was stirred at RT under N₂ for 18 h.The solvent was removed in vacuo and the crude product was washed withethyl acetate (8 ml) and dried in vacuo to yield1-{3-tert-butyl-1-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-yl}-3-(naphthalene-1-yl)ureaas a white solid (0.22 g). mp: 230 (dec.); ¹H NMR (200 MHz, DMSO-d₆): δ9.12 (s, 1H), 8.92 (s, 1H), 8.32-8.08 (m, 3H), 7.94-7.44 (m, 8H), 6.44(s, 1H), 3.51 (s, 2H), 1.31 (s, 9H); MS:

Example 26

The title compound was synthesized in a manner analogous to Example 23utilizing Example N (0.2 g, 0.73 mmol) and 4-chlorophenylisocyanate(0.112 g, 0.73 mmol) to yield1-{3-tert-butyl-1-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-yl}-3-(4-chlorophenyl)ureaas a white solid (0.28 g). mp: 222 224. (dec.); ¹H NMR (200 MHz,DMSO-d₆); δ 9.15 (s, 1H), 8.46 (s, 1H), 7.55-7.31 (m, 8H), 6.39 (s, 1H),3.48 (s, 2H), 1.30 (s, 9H); MS:

Example O

The title compound is synthesized in a manner analogous to Example Cutilizing Example A and 1-isocyanato-4-methoxy-naphthalene to yieldethyl3-(3-tert-butyl-5-(3-(1-methoxynaphthalen-4-yl)ureido)-1H-pyrazol-1-yl)benzoate.

Example 27

The title compound is synthesized in a manner analogous to Example 17utilizing Example M and D-4-phenyl-oxazolidin-2-one to yieldD-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-phenylurea.

Example 28

The title compound is synthesized in a manner analogous to Example 17utilizing Example M and L-4-phenyl-oxazolidin-2-one to yieldL-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-phenylurea.

Example P

A mixture of 3-(3-amino-phenyl)-acrylic acid methyl ester (6 g) and 10%Pd on activated carbon (1 g) in ethanol (50 ml) was hydrogenated at 30psi for 18 h and filtered over Celite. Removal of the volatiles in vacuoprovided 3-(3-amino-phenyl)propionic acid methyl ester (6 g).

A vigorously stirred solution of the crude material from the previousreaction (5.7 g, 31.8 mmol) dissolved in 6 N HCl (35 ml) was cooled to0° C., and sodium nitrite (2.2 g) in water (20 ml) was added. After 1 h,tin (II) chloride dihydrate (18 g) in 6 N HCl (35 ml) was added. And themixture was stirred at 0° C. for 3 h. The pH was adjusted to pH 14 withsolid KOH and extracted with EtOAc. The combined organic extracts wereconcentrated in vacuo provided methyl 3-(3-hydrazino-phenyl)propionate(1.7 g).

A stirred solution of the crude material from the previous reaction (1.7g, 8.8 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.2 g, 9.7 mmol) inethanol (30 ml) and 6 N HCl (2 ml) was refluxed for 18 h and cooled toRT. The volatiles were removed in vacuo and the residue dissolved inEtOAc and washed with 1 N aqueous NaOH. The organic layer was dried(Na₂SO₄) and concentrated in vacuo and the residue was purified bycolumn chromatography using 30% ethyl acetate in hexane as the eluent toprovide methyl3-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]propionate (3.2 g),which was used without further purification

Example 29

A mixture of Example P (0.35 g, 1.1 mmol) and 1-naphthylisocyanate (0.19g, 1.05 mmol) in dry CH₂Cl₂ (5 ml) was stirred at RT under N₂ for 20 h.The solvent was removed in vacuo and the residue was stirred in asolution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithiumhydroxide (0.1 g) for 3 h at RT, and subsequently diluted with EtOAc anddilute citric acid solution. The organic layer was dried (Na₂SO₄), andthe volatiles removed in vacuo. The residue was purified by columnchromatography using 3% methanol in CH₂Cl₂ as the eluent to yield3-(3-{3-tert-butyl-5-[3-(naphthalen-1-yl)ureido]-1H-pyrazol-1-yl)phenylpropionicacid (0.22 g, brownish solid). mp: 105-107; ¹H NMR (200 MHz, CDCl₃): δ7.87-7.36 (m, 10H), 7.18-7.16 (m, 1H), 6.52 (s, 1H), 2.93 (t, J=6.9 Hz,2H), 2.65 (t, J=7.1 Hz, 2H), 1.37 (s, 9H); MS

Example 30

The title compound was synthesized in a manner analogous to Example 29utilizing Example P (0.30 g, 0.95 mmol) and 4-chlorophenylisocyanate(0.146 g, 0.95 mmol) to yield3-(3-{3-tert-butyl-5-[3-(4-chlorophenyl)ureido]-1H-pyrazol-1-yl)phenyl)propionicacid (0.05 g, white solid). mp: 85 87; ¹H NMR (200 MHz, CDCl₃): δ8.21(s, 1H), 7.44-7.14 (m, 7H), 6.98 (s, 1H), 6.55 (s, 1H), 2.98 (t, J=5.2Hz, 2H), 2.66 (t, J=5.6 Hz, 2H), 1.40 (s, 9H); MS

Example Q

A mixture of ethyl 3-(4-aminophenyl)acrylate (1.5 g) and 10% Pd onactivated carbon (0.3 g) in ethanol (20 ml) was hydrogenated at 30 psifor 18 h and filtered over Celite. Removal of the volatiles in vacuoprovided ethyl 3-(4-aminophenyl)propionate (1.5 g).

A solution of the crude material from the previous reaction (1.5 g, 8.4mmol) was dissolved in 6 N HCl (9 ml), cooled to 0° C., and vigorouslystirred. Sodium nitrite (0.58 g) in water (7 ml) was added. After 1 h,tin (II) chloride dihydrate (5 g) in 6 N HCl (10 ml) was added. Thereaction mixture was stirred at 0° C. for 3 h. The pH was adjusted to pH14 with solid KOH and extracted with EtOAc. The combined organicextracts were concentrated in vacuo provided ethyl3-(4-hydrazino-phenyl)-propionate(1 g).

The crude material from the previous reaction (1 g, 8.8 mmol) and4,4-dimethyl-3-oxopentanenitrile (0.7 g) in ethanol (8 ml) and 6 N HCl(1 ml) was refluxed for 18 h and cooled to RT. The volatiles wereremoved in vacuo. The residue was dissolved in ethyl acetate and washedwith 1 N aqueous sodium hydroxide solution. The organic layer was dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by columnchromatography using 0.7% methanol in CH₂Cl₂ as the eluent to provideethyl3-{4-[3-tert-butyl-5-(3-(naphthalene-1-yl)ureido]-1H-pyrazol-1-yl}phenyl)propanoate(0.57 g).

Example 31

A mixture of Example Q (0.25 g, 0.8 mmol) and 1-naphthylisocyanate (0.13g, 0.8 mmol) in dry CH₂Cl₂ (5 ml) was stirred at RT under N₂ for 20 h.The solvent was removed in vacuo and the residue was stirred in asolution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithiumhydroxide (0.1 g) for 3 h at RT and diluted with EtOAc and dilutedcitric acid solution. The organic layer was dried (Na₂SO₄), and thevolatiles removed in vacuo. The residue was purified by columnchromatography using 4% methanol in CH₂Cl₂ as the eluent to yield3-{4-[3-tert-butyl-5-(3-(naphthalene-1-yl)ureido]-H-pyrazol-1-yl}phenyl)propanonicacid (0.18 g, off-white solid). mp: 120 122; ¹H NMR (200 MHz, CDCl₃): δ7.89-7.06 (m, 11H), 6.5 (s, 1H), 2.89 (m, 2H), 2.61 (m, 2H), 1.37 (s,9H); MS

Example 32

The title compound was synthesized in a manner analogous to Example 31utilizing Example Q (0.16 g, 0.5 mmol) and 4-chlorophenylisocyanate(0.077 g, 0.5 mmol) to yield3-{4-[3-tert-butyl-5-(3-(4-chlorophenyl)ureido]-1H-pyrazol-1-yl}phenyl)propanonicacid (0.16 g, off-white solid). mp: 112-114; ¹H NMR (200 MHz, CDCl₃): δ8.16 (s, 1H), 7.56 (s, 1H), 7.21 (s, 2H), 7.09 (s, 2H), 6.42 (s, 1H),2.80 (m, 2H), 2.56 (m, 2H), 1.32 (s, 9H); MS

Example R

A 250 mL pressure vessel (ACE Glass Teflon screw cap) was charged with3-nitrobiphenyl (20 g, 0.10 mol) dissolved in THF (˜100 mL) and 10% Pd/C(3 g). The reaction vessel was charged with H₂ (g) and purged threetimes. The reaction was charged with 40 psi H₂ (g) and placed on a Parrshaker hydrogenation apparatus and allowed to shake overnight at RT.HPLC showed that the reaction was complete thus the reaction mixture wasfiltered through a bed of Celite and evaporated to yield the amine: 16.7g (98% yield)

In a 250 mL Erlenmeyer flask with a magnetic stir bar, the crudematerial from the previous reaction (4.40 g, 0.026 mol) was added to 6 NHCl (40 mL) and cooled with an ice bath to ˜0° C. A solution of NaNO₂(2.11 g, 0.0306 mol, 1.18 eq.) in water (5 mL) was added drop wise.After 30 min, SnCl₂2H₂O (52.0 g, 0.23 mol, 8.86 eq.) in 6N HCl (100 mL)was added and the reaction mixture was allowed to stir for 3 h, thensubsequently transferred to a 500 mL round bottom flask. To this,4,4-dimethyl-3-oxopentanenitrile (3.25 g, 0.026 mol) and EtOH (100 ml)were added and the mixture refluxed for 4 h, concentrated in vacuo andthe residue extracted with EtOAc (2×100 mL). The residue was purified bycolumn chromatograph using hexane/EtOAc/Et₃N (8:2:0.2) to yield 0.53 gof Example R. ¹H NMR (CDCl₃): δ 7.5 (m, 18H), 5.8 (s, 1H), 1.3 (s, 9H).

Example 33

In a dry vial with a magnetic stir bar, Example R (0.145 g; 0.50 mmol)was dissolved in 2 mL CH₂Cl₂ (anhydrous) followed by the addition ofphenylisocyanate (0.0544 mL; 0.50 mmol; 1 eq.). The reaction was keptunder argon and stirred for 17 h. Evaporation of solvent gave acrystalline mass that was triturated with hexane/EtOAc (4:1) andfiltered to yield1-(3-tert-butyl-1-(3-phenylphenyl)-1H-pyrazol-5-yl)-3-phenylurea (0.185g, 90%). HPLC purity: 96%; mp: 80 84; ¹H NMR (CDCl₃): δ 7.3 (m, 16H),6.3 (s, 1H), 1.4 (s, 9H).

Example 34

The title compound was synthesized in a manner analogous to Example 33utilizing Example R (0.145 g; 0.50 mmol) and p-chlorophenylisocyanate(0.0768 g, 0.50 mmol, 1 eq.) to yield1-(3-tert-butyl-1-(3-phenylphenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea(0.205 g, 92%). HPLC purity: 96.5%; mp: 134 136; ¹H NMR (CDCl₃): δ 7.5(m, 14H), 7.0 (s, 1H), 6.6 (s, 1H), 6.4 (s, 1H), 1.4 (s, 9H).

Example S

The title compound is synthesized in a manner analogous to Example Cutilizing Example A and 4-fluorophenyl isocyanate yield ethyl3-(3-tert-butyl-5-(3-(4-fluorophenyl)ureido)-1H-pyrazol-1-yl)benzoate.

Example 35

The title compound is synthesized in a manner analogous to Example 17utilizing Example M and D-4-phenyl-oxazolidin-2-one to yieldD-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-(naphthalen-1-yl)urea.

Example 36

The title compound is synthesized in a manner analogous to Example 29utilizing Example P (0.30 g, 0.95 mmol) and 4-fluorophenylisocyanate(0.146 g, 0.95 mmol) to yield3-(3-(3-tert-butyl-5-(3-(4-fluorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoicacid.

Example T

To a stirred solution of Example N (2 g, 7.35 mmol) in THF (6 ml) wasadded borane-methylsulfide (18 mmol). The mixture was heated to refluxfor 90 min and cooled to RT, after which 6 N HCl was added and heated toreflux for 10 min. The mixture was basified with NaOH and extracted withEtOAc. The organic layer was dried (Na₂SO₄) filtered and concentrated invacuo to yield 3-tert-butyl-1-[3-(2-aminoethyl)phenyl]-1H-pyrazol-5amine (0.9 g).

A mixture of the crude material from the previous reaction (0.8 g, 3.1mmol) and di-tert-butylcarbonate (0.7 g, 3.5 mmol) and catalyticallyamount of DMAP in dry CH₂Cl₂ (5 ml) was stirred at RT under N₂ for 18 h.The reaction mixture was concentrated in vacuo and the residue waspurified by column chromatography using 1% methanol in CH₂Cl₂ as theeluent to yield tert-butyl3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenylcarbamate (0.5 g).

Example 37

A mixture of Example T (0.26 g, 0.73 mmol) and 1-naphthylisocyanate(0.123 g, 0.73 mmol) in dry CH₂Cl₂ (5 ml) was stirred at RT under N₂ for48 h. The solvent was removed in vacuo and the residue was purified bycolumn chromatography using 1% methanol in CH₂Cl₂ as the eluent (0.15 g,off-white solid). The solid was then treated with TFA (0.2 ml) for 5 minand diluted with EtOAc. The organic layer was washed with saturatedNaHCO₃ solution and brine, dried (Na₂SO₄), filtered and concentrated invacuo to yield1-{3-tert-butyl-1-[3-(2-Aminoethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)ureaas a solid (80 mg). mp: 110-112; ¹H NMR (200 MHz, DMSO-d₆): δ 9.09 (s,1H), 8.90 (s, 1H), 8.01-7.34 (m, 11H), 6.43 (s, 1H), 3.11 (m, 2H), 2.96(m, 2H), 1.29 (s, 9H); MS

Example 38

The title compound was synthesized in a manner analogous to Example 37utilizing Example T (0.15 g, 0.42 mmol) and 4-chlorophenylisocyanate(0.065 g, 0.42 mmol) to yield1-{3-tert-butyl-1-[3-(2-Aminoethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)ureaas an off-white solid (20 mg). mp: 125-127; ¹H NMR (200 MHz, CDCl₃): δ8.81 (s, 1H), 8.66 (s, 1H), 7.36-7.13 (m, 8H), 6.54 (s, 1H), 3.15 (brs,2H), 2.97 (brs, 2H), 1.32 (s, 9H); MS

Example U

In a 250 mL Erlenmeyer flask with a magnetic stir bar, m-anisidine (9.84g, 0.052 mol) was added to 6 N HCl (80 mL) and cooled with an ice bathto 0° C. A solution of NaNO₂ (4.22 g, 0.0612 mol, 1.18 eq.) in water (10mL) was added drop wise. After 30 min, SnCl₂.2H₂O (104.0 g, 0.46 mol,8.86 eq.) in 6 N HCl (200 mL) was added and the reaction mixture wasallowed to stir for 3 h., and then subsequently transferred to a 1000 mLround bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (8.00 g,0.064 mol) and EtOH (200 mL) were added and the mixture refluxed for 4h, concentrated in vacuo and the residue recrystallized from CH₂Cl₂ toyield 3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-amine as the HClsalt (13.9 g).

The crude material from the previous reaction (4.65 g, 0.165 mol) wasdissolved in 30 mL of CH₂Cl₂ with Et₃N (2.30 mL, 0.0165 mol, 1 eq.) andstirred for 30 min Extraction with water followed by drying of theorganic phase with Na₂SO₄ and concentration in vacuo yielded a brownsyrup that was the free base,3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-amine (3.82 g, 94.5%),which was used without further purification.

Example 39

In a dry vial with a magnetic stir bar, Example U (2.62 g, 0.0107 mol)was dissolved in CH₂Cl₂ (5 mL, anhydrous) followed by the addition of1-naphthylisocyanate (1.53 mL, 0.0107 mol, 1 eq.). The reaction was keptunder Ar and stirred for 18 h. Evaporation of solvent followed by columnchromatography with EtOAc/hexane/Et₃N (7:2:0.5) as the eluent yielded1-[3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-3-(naphthalen-1-yl)urea(3.4 g, 77%). HPLC: 97%; mp: 78-80; ¹H NMR (CDCl₃): δ 7.9-6.8 (m, 15H),6.4 (s, 1H), 3.7 (s, 3H), 1.4 (s, 9H).

Example 40

The title compound was synthesized in a manner analogous to Example 39utilizing Example U (3.82 g; 0.0156 mol) and p-chlorophenylisocyanate(2.39 g, 0.0156 mol, 1 eq.), purified by trituration with hexane/EtOAc(4:1) and filtered to yield1-[3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-3-(4-chlorophenyl)urea(6.1 g, 98%). HPLC purity: 95%; mp: 158-160; ¹H NMR (CDCl₃): δ 7.7 (s,1H); δ 7.2 6.8 (m, 8H), 6.4 (s, 1H), 3.7 (s, 3H), 1.3 (s, 9H).

Example 41

In a 100 ml round bottom flask equipped with a magnetic stir bar,Example 39 (2.07 g) was dissolved in CH₂Cl₂ (20 mL) and cooled to 0° C.with an ice bath. BBr₃ (1 M in CH₂Cl₂; 7.5 mL) was added slowly. Thereaction mixture was allowed to warm to RT overnight. Additional BBr₃ (1M in CH₂Cl₂, 2×1 mL, 9.5 mmol total added) was added and the reactionwas quenched by the addition of MeOH. Evaporation of solvent led to acrystalline material that was chromatographed on silica gel (30 g) usingCH₂Cl₂/MeOH (9.6:0.4) as the eluent to yield1-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-3-(naphthalene-1-yl)urea(0.40 g, 20%). ¹H NMR (DMSO-d₆): δ 9.0 (s, 1H), 8.8 (s, 1H), 8.1-6.8 (m,11H), 6.4 (s, 11H), 1.3 (s, 9H). MS (ESI) m/z: 401 (M+H⁺).

Example 42

The title compound was synthesized in a manner analogous to Example 41utilizing Example 40 (2.00 g, 5 mmol) that resulted in a crystallinematerial that was filtered and washed with MeOH to yield1-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-3-(4-chlorophenyl)urea(1.14 g, 60%). HPLC purity: 96%; mp: 214-216; ¹H NMR (CDCl₃): δ 8.4 (s,1H), 7.7 (s, 1H), 7.4-6.6 (m, 9H), 1.3 (s, 9H).

Example V

The starting material,1-[4-(aminomethyl)phenyl]-3-tert-butyl-N-nitroso-1H-pyrazol-5-amine, wassynthesized in a manner analogous to Example A utilizing4-aminobenzamide and 4,4-dimethyl-3-oxopentanenitrile.

A 1 L four-necked round bottom flask was equipped with a stir bar, asource of dry Ar, a heating mantle, and a reflux condenser. The flaskwas flushed with Ar and charged with the crude material from theprevious reaction (12 g, 46.5 mmol; 258.1 g/mol) and anhydrous THF (500ml). This solution was treated cautiously with LiAlH₄ (2.65 g, 69.8mmol) and the reaction was stirred overnight. The reaction was heated toreflux and additional LiAlH₄ was added complete (a total of 8.35 gadded). The reaction was cooled to 0 and H₂O (8.4 ml), 15% NaOH (8.4 ml)and H₂O (24 ml) were added sequentially; The mixture was stirred for 2h, the solids filtered through Celite, and washed extensively with THF,the solution was concentrated in vacuo to yield1-(4-(aminomethyl-3-methoxy)phenyl)-3-tert-butyl-1H-pyrazol-5-amine (6.8g) as an oil.

A 40 mL vial was equipped with a stir bar, a septum, and a source of Ar.The vial was charged with the crude material from the previous reaction(2 g, 8.2 mmol, 244.17 g/mol) and CHCl₃ (15 mL) were cooled to 0 underAr and di-tert-butylcarbonate (1.9 g, 9.0 mmol) dissolved in CHCl₃ (5mL) was added drop wise over a 2 min period. The mixture was treatedwith 1N KOH (2 mL), added over a 2 h period. The resulting emulsion wasbroken with the addition of saturated NaCl solution, the layers wereseparated and the aqueous phase extracted with CH₂Cl₂ (2×1.5 ml). Thecombined organic phases were dried over Na₂SO₄, filtered, concentratedin vacuo to yieldtert-butyl[4-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)-2-methoxybenzylcarbamate(2.23 g, 79%) as a light yellow solid. ¹H NRM (CDCl₃): δ 7.4 (m, 5H),5.6 (s, 1H), 4.4 (d, 2H), 1.5 (s, 9H), 1.3 (s, 9H).

Example 43

A 40 mL vial was equipped with a septum, a stir bar and a source of Ar,and charged with Example V (2 g, 5.81 mmol), flushed with Ar anddissolved in CHCl₃ (20 mL). The solution was treated with2-naphthylisocyanate (984 mg, 5.81 mmol) in CHCl₃ (5 mL) and added over1 min The reaction was stirred for 8 h, and additional1-naphthylisocyanate (81 mg) was added and the reaction stirredovernight. The solid was filtered and washed with CH₂Cl₂ to yieldtert-butyl4-[3-tert-butyl-5-(3-naphthalen-1-yl)ureido)-1H-pyrazol-1-yl]benzylcarbamate(1.2 g). HPLC purity: 94.4%; ¹H NMR (DMSO-d₆): δ 9.1 (s, 1H), 8.8 (s,1H), 8.0 (m, 3H), 7.6 (m, 9H), 6.4 (s, 1H), 4.2 (d, 2H), 1.4 (s, 9H),1.3 (s, 9H).

Example 44

The title compound was synthesized in a manner analogous to Example 43utilizing Example V (2.0 g, 5.81 mmol) and p-chlorophenylisocyanate (892mg) to yield tert-butyl4-[3-tert-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl]benzylcarbamate(1.5 g). HPLC purity: 97%; ¹H NMR (DMSO-d₆): δ 9.2 (s, 1H), 8.4 (s, 1H),7.4 (m, 8H), 6.4 (s, 1H), 4.2 (d, 2H), 1.4 (s, 9H), 1.3 (s, 9H).

Example 45

A 10 mL flask equipped with a stir bar was flushed with Ar and chargedwith Example 43 (770 mg, 1.5 mmol) and CH₂Cl₂ (1 ml) and 1:1 CH₂Cl₂:TFA(2.5 mL). After 1.5 h, reaction mixture was concentrated in vacuo, theresidue was dissolved in EtOAc (15 mL), washed with saturated NaHCO₃ (10mL) and saturated NaCl (10 mL). The organic layers was dried, filteredand concentrated in vacuo to yield1-{3-tert-butyl-1-[4-(aminomethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea(710 mg). ¹H NMR (DMSO-d₆): δ 7.4 (m, 11H), 6.4 (s, 1H), 3.7 (s, 2H),1.3 (s, 9H).

Example 46

The title compound was synthesized in a manner analogous to Example 45utilizing Example 44 (1.5 g, 1.5 mmol) to yield1-{3-tert-butyl-1-[4-(aminomethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea(1.0 g). HPLC purity: 93.6%; mp: 100-102; ¹H NMR (CDCl₃): δ 8.6 (s, 1H),7.3 (m, 8H), 6.3 (s, 1H), 3.7 (brs, 2H), 1.3 (s, 9H).

Example 47

A 10 ml vial was charged with Example 45 (260 mg, 63 mmol) and absoluteEtOH (3 mL) under Ar. Divinylsulfone (63 uL, 74 mg, 0.63 mmol) was addeddrop wise over 3 min and the reaction was stirred at RT for 1.5 h. andconcentrated in vacuo to yield a yellow solid, which was purified viapreparative TLC, developed in 5% MeOH:CH₂Cl₂. The predominant band wascut and eluted off the silica with 1:1 EtOAc:MeOH, filtered andconcentrated in vacuo to yield1-{3-tert-butyl-1-[4-(1,1-dioxothiomorpholin-4-yl)methylphenyl]-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea(150 mg). HPLC purity: 96%; ¹H NMR (DMSO-d₆): δ 9.1 (s, 1H), 9.0 (s,1H), 7.9 (m, 3H), 7.5 (m, 8H), 6.4 (s, 1H), 3.1 (brs, 4H), 2.9 (brs,4H), 1.3 (s, 9H).

Example 48

The title compound was synthesized in a manner analogous to Example 47utilizing Example 46 (260 mg, 0.66 mmol) to yield1-{3-tert-butyl-1-[4-(1,1-dioxothiomorpholin-4-yl)methylphenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea(180 mg). HPLC purity: 93%; mp: 136-138; ¹H NMR (DMSO-d₆): δ 9.2 (s,1H), 8.5 (s, 1H), 7.4 (m, 9H), 6.4 (s, 1H), 3.1 (brs, 4H), 3.0 (brs,4H), 1.3 (s, 9H).

Example 49

To a stirring solution of chlorosulfonyl isocyanate (0.35 g, 5 mmol) inCH₂Cl₂ (20 mL) at 0° C. was added pyrrolidine (0.18 g, 5 mmol) at such arate that the reaction temperature did not rise above 5° C. Afterstirring for 2 h, a solution of Example 41 (1.10 g, 6.5 mmol) andtriethylmine (0.46 g, 9 mmol) in CH₂Cl₂ (20 mL) was added. When theaddition was complete, the mixture was allowed to warm to RT and stirredovernight. The reaction mixture was poured into 10% HCl (10 mL)saturated with NaCl, the organic layer was separated and the aqueouslayer extracted with ether (20 mL). The combined organic layers weredried (Na₂SO₄) and concentrated in vacuo, purified by preparative HPLCto yield (pyrrolidine-1-carbonyl)sulfamic acid3-[3-tert-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]phenyl ester(40 mg). ¹H NMR (CDCl₃): δ 9.12 (brs, 1H), 8.61 (brs, 1H), 7.85-7.80 (m,3H), 7.65 (d, J=8.0 Hz, 2H), 7.53-7.51 (m, 1H), 7.45-7.25 (m, 5H), 6.89(s, 4H), 3.36-3.34 (brs, 1H), 3.14-3.13 (brs, 2H), 1.69 (brs, 2H), 1.62(brs, 2H), 1.39 (s, 9H); MS (ESI) m/z: 577 (M+H⁺).

Example 50

The title compound was synthesized in a manner analogous to Example 49utilizing Example 42 to yield (pyrrolidine-1-carbonyl)sulfamic acid3-[3-tert-butyl-5-(4-chlorophenyl-1-yl-ureido)pyrazol-1-yl]phenyl ester.MS (ESI) m/z: 561 (M+H⁺).

Example W

Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended intoluene (100 mL) and treated with triethylamine (20.2 g). The mixturewas stirred at RT for 30 min and treated with pivaloylacetonitrile (18g). The reaction was heated to reflux and stirred overnight. The hotmixture was filtered, the solids washed with hexane and dried in vacuoto afford 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (25 g,70%). ¹H NMR (DMSO-d₆): δ 7.5 (d, 2H), 7.0 (d, 1H), 6.4 (s, 1H), 6.1 (s,2H), 3.9 (s, 3H), 1.3 (s, 9H).

Example 51

To a solution of 1-isocyanato-4-methoxy-naphthalene (996 mg) inanhydrous CH₂Cl₂ (20 mL) of was added Example W (1.23 g). The reactionsolution was stirred for 3 h, the resulting white precipitate filtered,treated with 10% HCl and recrystallized from MeOH, and dried in vacuo toyield1-[3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-3-(1-methoxynaphthalen-4-yl-ureaas white crystals (900 mg, 40%). HPLC purity: 96%; mp: 143-144; ¹H NMR(DMSO-d₆): δ 8.8 (s, 1H), 8.5 (s, 1H), 8.2 (d, 1H), 8.0 (d, 1H), 7.6 (m,5H), 7.1 (d, 2H), 7.0 (d, 1H), 6.3 (s, 1H), 4.0 (s, 3H), 3.9 (s, 3H);1.3 (s, 9H).

Example 52

The title compound was synthesized in a manner analogous to Example 51utilizing Example W and p-bromophenylisocyanate (990 mg) to yield1-{3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl}-3-(4-bromophenyl)ureaas off-white crystals (1.5 g, 68%). HPLC purity: 98%; mp: 200-201; ¹HNMR (DMSO-d₆): δ 9.3 (s, 1H), 8.3 (s, 1H), 7.4 (m, 6H), 7.0 (d, 2H), 6.3(s, 1H), 3.8 (s, 3H), 1.3 (s, 9H).

Example 53

The title compound was synthesized in a manner analogous to Example 51utilizing Example W and p-chlorophenylisocyanate (768 mg) into yield1-{3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl}-3-(4-chlorophenyl)ureaas white crystals (1.3 g, 65%). HPLC purity: 98%; mp: 209-210; ¹H NMR(DMSO-d₆): δ 9.1 (s, 1H), 8.3 (s, 1H), 7.4 (m, 4H), 7.3 (d, 2H), 7.1 (d,2H), 6.3 (s, 1H), 3.8 (s, 3H), 1.3 (s, 9H).

Example 54

The title compound was synthesized in a manner analogous to Example 41utilizing Example 53 (500 mg) to yield1-{3-tert-butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl}-3-(4-chlorophenyl)ureaas white crystals (300 mg, 62%). HPLC purity: 94%; mp: 144-145; ¹H NMR(DMSO-d₆): δ 9.7 (s, 1H), 9.1 (s, 1H), 8.3 (s, 1H), 7.4 (d, 2H), 7.3 (m,4H); 6.9 (d, 2H), 6.3 (s, 1H), 1.3 (s, 9H)

Example 55

The title compound was synthesized in a manner analogous to Example 41utilizing Example 52 (550 mg) to yield1-{3-tert-butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl}-3-(4-bromophenyl)ureaas a white crystalline solid (400 mg, 70%). HPLC purity: 93%; mp: 198200; ¹H NMR (DMSO-d₆): δ 9.7 (s, 1H), 9.2 (s, 1H), 8.3 (s, 1H), 7.4 (d,4H), 7.2 (m, 2H), 6.9 (d, 2H), 6.3 (s, 1H), 1.3 (s, 9H).

Example X

Methyl 4-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)benzoate (3.67 mmol) wasprepared from methyl 4-hydrazinobenzoate and pivaloylacetonitrile by theprocedure of Regan, et al., J. Med. Chem., 45, 2994 (2002).

Example 56

A 500 mL round bottom flask was equipped with a magnetic stir bar and anice bath. The flask was charged with Example X (1 g) and this wasdissolved in CH₂Cl₂ (100 mL). Saturated sodium bicarbonate (100 mL) wasadded and the mixture rapidly stirred, cooled in an ice bath and treatedwith diphosgene (1.45 g) and the heterogeneous mixture stirred for 1 h.The layers were separated and the CH₂Cl₂ layer treated with tert-butanol(1.07 g) and the solution stirred overnight at RT. The solution waswashed with H₂O (2×150 mL), dried (Na₂SO₄), filtered, concentrated invacuo, and purified by flash chromatography using 1:2 ethylacetate:hexane as the eluent to yield tert-butyl1-(4-(methoxycarbonyl)phenyl)-3-tert-butyl-1H-pyrazol-5-ylcarbamate (100mg) as an off-white solid. ¹HNMR (DMSO-d₆): δ 9.2 (s, 1H), 8.1 (d, 2H),7.7 (d, 2H), 6.3 (s, 1H), 3.3 (s, 3H), 1.3 (s, 18H).

Example 57

The title compound was synthesized in a manner analogous to Example 41utilizing Example X (1.37 g) and p-chlorophenylisocyanate (768 mg) toyield methyl4-{3-tert-butyl-5-[3-(4-chlorophenyl)ureido]-1H-pyrazol-1-yl}benzoate aswhite crystals (1.4 g 66%). HPLC purity: 98%; mp: 160-161; ¹H NMR(DMSO-d₆): δ 9.2 (s, 1H), 8.6 (s, 1H), 8.1 (d, 2H), 7.8 (d, 2H), 7.5 (d,2H), 7.3 (d, 2H), 6.4 (s, 1H), 3.9 (s, 3H), 1.3 (s, 9H).

Example 58

The title compound was synthesized in a manner analogous to Example 41utilizing Example X (1.27 g) and 1-isocyanato-4-methoxy-naphthalene (996mg) to yield methyl4-{3-tert-butyl-5-[3-(1-methoxynaphthalen-4-yl)ureido]-1H-pyrazol-1-yl}benzoateas white crystals (845 mg, 36%). HPLC purity: 98%; mp: 278 280; ¹H NMR(DMSO-d₆): δ 8.76 (s, 1H), 8.73 (s, 1H), 8.1 (m, 3H), 7.9 (d, 1H), 7.7(d, 2H), 7.6 (m, 3H), 7.0 (d, 1H), 7.0 (d, 1H), 6.3 (s, 1H), 4.0 (s,3H), 3.9 (s, 3H), 1.3 (s, 9H).

Example 59

The title compound was synthesized in a manner analogous to Example 41utilizing Example X (1.37 g) and p-bromophenylisocyanate (990 mg) toyield methyl4-{3-tert-butyl-5-[3-(4-bromophenyl)ureido]-1H-pyrazol-1-yl}benzoate aswhite crystals (1.4 g, 59%). HPLC purity: 94%; mp: 270 272; ¹H NMR(DMSO-d₆): δ 9.2 (s, 1H), 8.6 (s, 1H), 8.1 (d, 2H), 7.7 (d, 2H), 7.4 (d,4H), 6.4 (s, 1H), 3.9 (s, 3H), 1.3 (s, 9H).

Example 60

To a solution of Example 59 (700 mg) in 30 mL of toluene at −78° C., wasadded dropwise a solution of diisobutylaluminum hydride in toluene (1Min toluene, 7.5 mL) over 10 min. The reaction mixture was stirred for 30min at −78° C., and then 30 min at 0° C. The reaction mixture wasconcentrated in vacuo to dryness and treated with H₂O. The solid wasfiltered and treated with acetomitrile. The solution was evaporated todryness and the residue was dissolved in ethyl acetate, and precipitatedby hexanes to afford yellow solid which was dried under vacuum to give1-[3-tert-butyl-1-(4-hydroxymethyl)phenyl)-1H-pyrazol-5-yl]urea (400 mg,61%). HPLC purity: 95%; ¹H NMR (DMSO-d₆): δ 9.2 (s, 1H), 8.4 (s, 1H),7.5 (m, 8H), 6.4 (s, 1H), 5.3 (t, 1H), 4.6 (d, 2H), 1.3 (s, 9H).

Wherein Y is O, S, NR6, —NR6SO2—, NR6CO—, alkylene, O—(CH2)n—,NR6-(CH2)n—, wherein one of the methylene units may be substituted withan oxo group, or Y is a direct bond; D is taken from the groupsidentified in Chart I:

wherein X or Y is O, S, NR6, —NR6SO2—, NR6CO—, alkylene, O—(CH2)n-,NR6—(CH2)n-, wherein one of the methylene units may be substituted withan oxo group, or X or Y is a direct bond; D is taken from the groupsidentified in Chart 1:

Specific examples of the present invention are illustrated by theirstructural formulae below:

Example Y

To a solution of 3-nitro-benzaldehyde (15.1 g, 0.1 mol) in CH₂Cl₂ (200mL) was added (triphenyl-15-phosphanylidene)-acetic acid ethyl ester(34.8 g, 0.1 mol) in CH₂Cl₂ (100 mL) dropwise at 0° C., which wasstirred for 2 h. After removal the solvent under reduced pressure, theresidue was purified by column chromatography to afford3-(3-nitro-phenyl)-acrylic acid ethyl ester (16.5 g, 74.6%) ¹H-NMR (400MHz, CDCl₃): 8.42 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.82 (d, J=7.6 Hz,1H), 7.72 (d, J=16.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 6.56 (d, J=16.0Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 1.36 (t, J=6.8 Hz, 3H).

A mixture of 3-(3-nitro-phenyl)-acrylic acid ethyl ester (16.5 g, 74.6mmol) and Pd/C (1.65 g) in methanol (200 mL) was stirred under 40 psi ofH₂ at RT for 2 h then filtered over celite. After removal the solvent,14 g of 3-(3-amino-phenyl)-propionic acid ethyl ester was obtained andused directly without further purification. ¹H-NMR (400 MHz, CDCl₃):7.11 (t, J=5.6 Hz, 1H), 6.67 (d, J=7.2 Hz, 1H), 6.63-6.61 (m, 2H), 4.13(q, J=7.2 Hz, 2H), 2.87 (t, J=8.0 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.34(t, J=6.8 Hz, 3H).

To a solution of 3-(3-amino-phenyl)-propionic acid ethyl ester (14 g,72.5 mmol) in concentrated HCl (200 mL) was added an aqueous solution(10 mL) of NaNO₂ (5 g, 72.5 mmol) at 0° C. and the resulting mixture wasstirred for 1 h. A solution of SnCl₂.2H₂O (33 g, 145-mmol) inconcentrated HCl (150 mL) was then added at 0° C. The reaction solutionwas stirred for an additional 2 h at RT. The precipitate was filteredand washed with ethanol and ether to give3-(3-hydrazino-phenyl)-propionic acid ethyl ester as a white solid,which was used without further purification.

Example Z

A mixture of Example Y (13 g, 53.3 mmol) and4,4-dimethyl-3-oxo-pentanenitrile (6.9 g, 55 mol) in ethanol (150 mL)was heated to reflux overnight. The reaction solution was evaporatedunder reduced pressure. The residue was purified by columnchromatography to give3-[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-propionic acid ethyl ester(14.3 g, 45.4 mmol) as a white solid. ¹H NMR (DMSO-d₆): 7.39-7.32 (m,3H), 7.11 (d, J=6.8 Hz, 1H), 5.34 (s, 1H), 5.16 (s, 2H), 4.03 (q, J=7.2Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.19 (s, 9H),1.15 (t, J=7.2 Hz, 3H).

Example 145

A solution of 4-fluoro-phenylamine (111 mg, 1.0 mmol) and CDI (165 mg,1.0 mmol) in DMF (2 mL) was stirred at RT for 30 min, and was then addedto a solution of Example Z (315 mg, 1.0 mmol) in DMF (2 mL). Theresulting mixture was stirred at RT overnight then added to water (50mL). The reaction mixture was extracted with ethyl acetate (3×50 mL) andthe combined organic extracts were washed with brine, dried (NaSO₄) andfiltered. After concentrated under reduced pressure, the residue waspurified by flash chromatography to afford3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionicacid ethyl ester (150 mg, 33%). ¹H-NMR (CDCl₃): 7.91 (s, 1H), 7.42 (d,J=4.8 Hz, 1H), 7.37-7.34 (m, 2H), 7.28 (s, 1H), 7.17-7.16 (m, 2H), 6.98(t, J=8.8 Hz, 2H), 6.59 (s, 1H), 4.04 (q, J=7.2 Hz, 2H), 3.03 (t, J=7.2Hz, 2H), 2.77 (t, J=7.2 Hz, 2H), 1.36 (s, 9H), 1.17 (t, J=7.2 Hz, 3H);MS (ESI) m/z: 453 M+H⁺).

Example 146

A solution of Example 145 (45 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH(3 mL) was stirred at RT overnight. The reaction mixture was neutralizedto pH=4, extracted with ethyl acetate (3×20 mL), the combined organicextracts were washed with brine, dried (NaSO₄) and filtered. Thefiltrate was concentrated to afford3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionicacid, (37 mg, 90%). ¹H NMR (CD₃OD): 7.63-7.62 (m, 2H), 7.56 (s, 1H),7.53-7.48 (m, 1H), 7.41-7.38 (m, 2H), 7.04 (t, J=8.8 Hz, 2H), 5.49 (s,1H), 3.07 (t, J=7.6 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 1.42 (s, 9H); MS(ESI) m/z: 415 (M+H⁺).

Example 147

A mixture of 4-methoxy-phenylamine (123 mg, 1.0 mmol) and CDI (165 mg,1.0 mmol) in DMF (2 mL) was stirred at RT for 30 min, and was then addeda solution of Example Z (315 mg, 1.0 mmol) in DMF (2 mL). The resultingmixture was stirred at RT overnight then quenched with of water (50 mL).The reaction mixture was extracted with ethyl acetate (3×50 mL) and thecombined organic extracts were washed with brine, dried (NaSO₄),filtered, concentrated under reduced presume to yield a residue whichwas purified by flash chromatography to afford3-(3-{3-t-butyl-5-[3-(4-methoxy-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionicacid ethyl ester (210 mg, 45%). ¹H-NMR (CD₃OD): 7.46 (t, J=7.6 Hz, 1H),7.38 (s, 1H), 7.34 (d, J=7.6 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 6.84 (d,J=8.4 Hz, 2H), 6.38 (s, 11H), 4.09 (q, J=7.2 Hz, 2H), 3.75 (s, 31H),3.00 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 1.33 (s, 9H), 1.20 (t,J=7.6 Hz, 3H); MS (ESI) m/z: 465 (M+H⁺).

Example 148

Utilizing the same synthetic procedure as for Example 61 and startingwith Example 147,3-(3-{3-t-butyl-5-[3-(4-methoxy-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionicacid is synthesized.

Example 149

A solution of isoquinoline-1-carboxylic acid (346 mg, 2.0 mmol), ExampleZ (315 mg, 1.0 mmol), EDCI (394 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol),and NMM (1.0 mL) in DMF (10 mL) was stirred at RT overnight. Afterquenching with water (100 mL), the reaction mixture was extracted withethyl acetate (3×100 mL). The combined organic extracts were washed withbrine, dried (NaSO₄), filtered and concentrated under reduced pressureto yield a residue which was purified by flash chromatography to afford3-(3-{3-t-butyl-5-[(isoquinoline-1-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid ethyl ester, (380 mg, 80%). ¹H-NMR (DMSO-d₆): 8.83 (d, J=8.4 Hz,1H), 8.85 (d, J=5.2 Hz, 1H), 8.09 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.82(t, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J=8.0Hz, 1H), 7.39 (t, J=5.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.57 (s, 1H),3.98 (q, J=7.2 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H),1.32 (s, 9H), 1.10 (t, J=7.6 Hz, 1H); MS (ESI) m/z: 471 (M+H⁺).

Example 150

A solution of Example 149u (47 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH(3 mL) was stirred at RT overnight. The reaction mixture was neutralizedto pH=4, extracted with ethyl acetate (3×20 mL), and the combinedorganic extracts were washed with brine, dried (NaSO₄) and filtered. Thefiltrate was concentrated to afford3-(3-{3-t-butyl-5-[(isoquinoline-1-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid, (39 mg, 87%). ¹H-NMR (DMSO-d₆): 10.77 (s, 1H), 9.68 (d, J=7.6 Hz,1H), 8.44 (d, J=5.2 Hz, 1H), 7.89-7.44 (m, 2H), 7.78-7.74 (m, 2H),7.49-7.47 (m, 3H), 7.30-7.27 (m, 3H), 6.95 (s, 1H), 3.05 (t, J=7.2 Hz,2H), 2.75 (t, J=7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 443 (M+H⁺).

Example 151

A solution of pyridine-2-carboxylic acid (246 mg, 2.0 mmol), Example Z(315 mg, 1.0 mmol), EDCI (394 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol),NMM (1.0 mL) in DMF (10 mL) was stirred at RT overnight. After quenchingwith water (100 mL), the reaction mixture was extracted with ethylacetate (3×100 mL). The combined organic extracts were washed withbrine, dried (NaSO₄), filtered and concentrated under reduced pressureto yield a residue which was purified by flash chromatography to afford3-(3-{3-t-butyl-5-[(pyridine-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid ethyl ester (300 mg, 70%). ¹H-NMR (CDCL₃): 8.53 (d, J=4.4 Hz, 1H),8.26 (d, J=7.2 Hz, 1H), 7.90 (t, J=8.0 Hz, 1H), 7.48-7.43 (m, 4H), 7.27(s, 1H), 6.87 (s, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H),2.71 (t, J=7.6 Hz, 2H), 1.39 (s, 9H), 1.24 (t, J=7.2 Hz, 3H); MS (ESI)m/z: 421 (M+H⁺).

Example 152

A solution of Example Z (315 mg, 1.0 mmol) and Barton's base (0.5 mL) inanhydrous CH₂Cl₂ (5 mL) under N₂ was stirred at RT for 30 min, and thenadded to a solution of naphthalene-1-carbonyl fluoride (348 mg, 0.2mmol) in anhydrous CH₂Cl₂ (5 mL). The resulting mixture was stirred atRT overnight. After quenching with water (100 mL), the reaction mixturewas extracted with ethyl acetate (3×100 mL). The combined organicextracts were washed with brine, dried NaSO₄), filtered and concentratedunder reduced pressure to yield a residue which was purified by flashchromatography to afford3-(3-{3-t-butyl-5-[(naphthalene-1-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid ethyl ester, (350 mg, 74%). ¹H-NMR (CDCL₃): 8.29 (d, J=8.0 Hz, 1H),7.98 (d, J=7.2 Hz, 2H), 7.89 (d, J=7.2 Hz, 1H), 7.62-7.57 (m, 3H),7.49-7.28 (m, 4H), 7.03 (s, 1H), 3.94 (q, J=7.2 Hz, 2H), 2.96 (t, J=7.2Hz, 2H), 2.58 (t, J=7.2 Hz, 2H), 1.45 (s, 9H), 1.13 (t, J=7.2 Hz, 3H);MS (ESI) m/z: 470 (M+H⁺).

Example 153

A solution of Example 152 (47 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH(3 mL) was stirred at RT overnight. The reaction mixture was neutralizedto pH=4, and extracted with ethyl acetate (3×20 mL). The combinedorganic extracts were washed with brine, and dried (NaSO₄) and filtered.The filtrate was concentrated to afford3-(3-{3-t-butyl-5-[(isoquinoline-1-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid, (38 mg, 86%). ¹H NMR (DMSO-d6): 7.99 (d, J=8.0 Hz, 1H), 7.90 (m,2H), 7.62 (m, 1H), 7.54-7.42 (m, 6H), 7.35 (m, 1H), 6.54 (s, 1H), 2.94(t, J=7.6 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 1.38 (s, 9H); MS (ESI) m/z:443 (M+H⁺).

Example 154

A solution of naphthalene-2-carboxylic acid (344 mg, 2.0 mmol) in SOCl₂(10 mL) was heated to reflux for 2 h. After concentration under reducedpressure, the residue was dissolved into CH₂Cl₂ (5 mL) and was droppedinto a solution of Example Z (315 mg, 1.0 mmol) in CH₂Cl₂ (10 mL) at 0°C., and was then stirred at RT overnight. After quenching with water (50mL), the reaction mixture was extracted with CH₂Cl₂ (3×100 mL). Thecombined organic extracts were washed with brine, dried (NaSO₄),filtered and concentrated under reduced pressure to yield a residuewhich was purified by flash chromatography to afford3-(3-{3-t-butyl-5-[(naphthalene-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid ethyl ester (180 mg, 38%). ¹H-NMR (CDCL₃): 8.24 (s, 1H), 8.21 (s,1H), 7.91 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.4 Hz,1H), 7.63-7.49 (m, 3H), 7.45-7.26 (m, 3H), 6.94 (s, 1H), 4.02 (q, J=7.2Hz, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.43 (s, 9H),1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 470 (M+H⁺).

Example 155

A solution of Example 154 (47 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH(3 mL) was stirred at RT overnight. The reaction mixture was neutralizedto pH=4, and extracted with ethyl acetate (3×20 mL). The combinedorganic extracts were washed with brine, and dried (NaSO₄) and filtered.The filtrate was concentrated to afford3-(3-{3-t-butyl-5-[(isoquinoline-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid, (37 mg, 84%). ¹H-NMR (CDCL3): 8.25 (s, 1H), 8.18 (s, 1H),7.91-7.86 (m, 3H), 7.75 (d, J=8.0 Hz, 1H), 7.59-7.55 (m, 2H), 7.48-7.39(m, 3H), 7.28 (s, 1H), 6.81 (s, 1H), 3.02 (t, J=7.6 Hz, 2H), 2.69 (t,J=7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 442 (M+H⁺).

Example 156

A solution of isoquinoline-3-carboxylic acid (346 mg, 2.0 mmol), exampleZ (315 mg, 1.0 mmol), EDCI (394 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol),and NMM (1.0 mL) in DMF (10 mL) was stirred at RT overnight. Afterquenching with water (50 mL), the reaction mixture was extracted withethyl acetate (3×100 mL). The combined organic extracts were washed withbrine, dried (NaSO₄) and filtered. After concentrated under reducedpressure, the residue was purified by flash chromatography to afford3-(3-{3-t-butyl-5-[(isoquinoline-3-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid ethyl ester (250 mg, 54%). ¹H-NMR (CD₃OD): 9.24 (s, 1H), 8.63 (s,1H), 8.17 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.88 (t, J=7.6 Hz,1H), 7.81 (t, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.54(d, J=7.6 Hz, 2H), 7.36 (d, J=7.6 Hz, 1H), 6.75 (s, 1H), 4.04 (q, J=7.6Hz, 2H), 3.01 (t, J=7.6 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H), 1.39 (s, 9H),1.14 (t, J=7.6 Hz, 3H); MS (ESI) m/z: 471 (M+H⁺).

Example 157

A solution of Example 156 (47 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH(3 mL) was stirred at RT overnight. The reaction mixture was neutralizedto pH=4, and extracted with ethyl acetate (3×20 mL). The combinedorganic extracts were washed with brine, and dried (NaSO₄) and filtered.The filtrate was concentrated to afford3-(3-{3-t-butyl-5-[(isoquinoline-3-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid, (39 mg, 88%). ¹H NMR (CDCL3): 10.49 (s, 1H), 9.16 (s, 1H), 8.69(s, 1H), 8.03 (d, J=7.6 Hz, 2H), 7.81 (t, J=7.2 Hz, 1H), 7.73 (t, J=7.2Hz, 1H), 7.48-7.39 (m, 3H), 7.28 (br s, 1H), 6.94 (s, 1H), 3.02 (t,J=7.6 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 442(M+H⁺).

Example 158

A solution of 4-chlorobenzoic acid (312 mg, 2.0 mmol) in SOCl₂ (10 mL)was heated to reflux for 2 h. After removal of the solvent, the residuewas dissolved into CH₂Cl₂ (5 mL) and was dropped into a solution ofExample Z (315 mg, 1.0 mmol) in CH₂Cl₂ (10 mL) at 0° C., was thenstirred at RT overnight. After quenching with water (50 mL), thereaction mixture was extracted with CH₂Cl₂ (3×100 mL). The combinedorganic extracts were washed with brine, dried (NaSO₄) and filtered.After concentrated under reduced pressure, the residue was purified byflash chromatography to afford3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionicacid ethyl ester (290 mg, 64%). ¹H-NMR (CDCL₃): 8.02 (s, 1H), 7.67 (d,J=8.4 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.36 (t,J=8.4 Hz, 3H), 6.87 (s, 1H), 4.06 (q, J=7.6 Hz, 2H), 3.02 (t, J=7.6 Hz,2H), 2.67 (t, J=7.6 Hz, 2H), 1.40 (s, 9H), 1.12 (t, J=7.6 Hz, 3H); MS(ESI) m/z: 454 (M+H⁺).

Example 159

A solution of Example 158 (45 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH(3 mL) was stirred at RT overnight. The reaction mixture was neutralizedto pH=4, and extracted with ethyl acetate (3×20 mL). The combinedorganic extracts were washed with brine, and dried (NaSO₄) and filtered.The filtrate was concentrated to afford3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionicacid, (38.5 mg, 87%). ¹H NMR (DMSO-d6): 10.38 (s, 1H), 7.85 (d, J=8.4Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.39 (s, 1H), 7.32 (d, J=4.8 Hz, 2H),7.15 (t, J=4.8 Hz, 1H), 6.38 (s, 1H), 2.80 (t, J=7.6 Hz, 2H), 2.44 (t,J=7.2 Hz, 2H), 1.29 (s, 9H); MS (ESI) m/z: 426 (M+H⁺).

Example AA

To a solution of m-aminobenzoic acid (200.0 g, 1.46 mmol) inconcentrated HCl (200 mL) was added an aqueous solution (250 mL) ofNaNO₂ (102 g, 1.46 mmol) at 0° C. and the reaction mixture was stirredfor 1 h. A solution of SnCl₂.2H₂O (662 g, 2.92 mmol) in concentrated HCl(2000 mL) was then added at 0° C. The reaction solution was stirred foran additional 2 h at RT. The precipitate was filtered and washed withethanol and ether to give 3-hydrazino-benzoic acid hydrochloride as awhite solid, which was used for the next reaction without furtherpurification. ¹H NMR (DMSO-d₆): 10.85 (s, 3 H), 8.46 (s, 1H), 7.53 (s,1H), 7.48 (d, J=7.6 Hz, 1H), 7.37 (m, J=7.6 Hz, 1H), 7.21 (d, J=7.6 Hz,1H).

A mixture of 3-hydrazino-benzoic acid hydrochloride (200 g, 1.06 mol)and 4,4-dimethyl-3-oxo-pentanenitrile (146 g, 1.167 mol) in ethanol (2L) was heated to reflux overnight. The reaction solution was evaporatedunder reduced pressure. The residue was purified by columnchromatography to give 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acidethyl ester (116 g, 40%) as a white solid together with3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid (93 g, 36%).3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid and ethyl ester: ¹H NMR(DMSO-d₆): 8.09 (s, 1H), 8.05 (brd, J=8.0 Hz, 1H), 7.87 (br d, J=8.0 Hz,1H), 7.71 (t, J=8.0 Hz, 1H), 5.64 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.34(t, J=7.2 Hz, 3H), 1.28 (s, 9H).

Example BB

To a stirred solution of Example AA (19.5 g, 68.0 mmol) in THF (200 mL)was added LiAlH₄ powder (5.30 g, 0.136 mol) at −10° C. under N₂. Themixture was stirred for 2 h at RT and excess LiAlH₄ was destroyed byslow addition of ice. The reaction mixture was acidified to pH=7 withdiluted HCl, the solution concentrated under reduced pressure, and theresidue was extracted with ethyl acetate. The combined organic extractswere concentrated to give[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-methanol (16.35 g, 98%) as awhite powder. ¹H NMR (DMSO-d6): 9.19 (s, 1H), 9.04 (s, 1H), 8.80 (s,1H), 8.26-7.35 (m, 1H), 6.41 (s, 1H), 4.60 (s, 2H), 1.28 (s, 9H); MS(ESI) m/z: 415 (M+H⁺).

Example CC

A solution of Example BB (13.8 g, 56.00 nmol) and SOCl₂ (8.27 mL, 0.11mol) in THF (200 mL) was refluxed for 3 h and concentrated under reducedpressure to yield5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-ylamine (14.5 g, 98%)as white powder which was used without further purification. ¹H NMR(DMSO-d₆), δ7.62 (s, 1 H), 7.53 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz,1H), 7.31 (d, J=7.2 Hz, 1H), 5.38 (s, 1 H), 5.23 (br s, 2H), 4.80 (s,2H), 1.19 (s, 9H). MS (ESI) m/z: 264 (M+H⁺).

Example DD

To a stirred solution of chlorosulfonyl isocyanate (1.43 g, 10.0 mmol)in CH₂Cl₂ (20 mL) at 0° C. was added 2-methyl-propan-2-ol (0.74 g, 10.0mmol) at such a rate that the reaction solution temperature did not riseabove 5° C. After being stirred for 1.5 h, a solution of glycine ethylester (1.45 g, 12.0 mmol) and Et₃N (3.2 mL, 25.0 mmol) in CH₂Cl₂ (20 mL)was added at such a rate that the reaction temperature didn't rise above5° C. When the addition was completed, the solution was warmed to RT andstirred overnight. The reaction mixture was poured into 10% HCl andextracted with CH₂Cl₂. The organic layer was washed with saturated NaCl,dried (Mg₂SO₄) and filtered. After removal of the solvent, the crudeproduct was washed with CH₂Cl₂ to afford ethyl2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate (2.4 g, 85%). ¹H-NMR(DMSO): δ 10.85 (s, 1H), 8.04 (t, J=6.0 Hz, 1H), 4.07 (q, J=5.6 Hz, 2H),3.77 (d, J=6.0 Hz, 2H), 1.40 (s, 9H), 1.18 (t, J=7.2 Hz, 3H).

To a solution of (4-methoxyphenyl)-methanol (1.4 g, 8.5 mmol) andtriphenyl-phosphane (2.6 g, 8.5 mol) in dry THF was added a solution ofethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previousstep (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at0° C. under N₂ atmosphere. The mixture was stirred at 0° C. for 2 h,warmed to RT and stirred overnight. After the solvent was removed invacuo, the residue was purified by column chromatography to afford ethyl2-((N-(butyloxycarbonyl)-N-(p-methoxybenzyl)sulfamoyl)amino)acetate (2.3g, 69%) as a white solid. ¹H-NMR (CDCl₃): δ 7.32 (d, J=8.8 Hz, 2H), 6.85(d, J=8.8 Hz, 2H), 5.71 (m, 1H), 4.76 (s, 2H), 4.14 (q, J=7.2 Hz, 2H),3.80 (s, 3H), 3.55 (d, J=5.2 Hz, 2H), 1.54 (s, 9H), 1.25 (t, J=7.2 Hz,3H).

To a solution of HCl in methanol (2 M) was added ethyl2-((N-(butyloxycarbonyl)-N-(p-methoxybenzyl)sulfamoyl)amino)acetate fromthe previous step (2.0 g, 5.0 mmol) in portions at RT and the mixturewas stirred for 3 h. After the solvent was removed in vacuo, the residuewas washed with diethyl ether to afford ethyl2-((N-(p-methoxybenzyl)sulfamoyl)amino)acetate (1.0 g, 70%). ¹H-NMR(DMSO-d₆): δ 7.43 (t, J=6.0 Hz, 1H), 7.287 (t, J=6.4 Hz, 1H), 7.21 (d,J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 3.94 (d, J=4.8 Hz, 2H), 3.71 (s,3H), 3.64 (d, J=6.0 Hz, 2H), 3.62 (s, 3H),

To a solution of ethyl 2-((N-(p-methoxybenzyl)sulfamoyl)amino)acetatefrom the previous step (1.0 g, 3.47 mmol) in DMF (50 mL) was addedKO-t-Bu (1.56 g, 13.88 mmol) in portions under N₂ atmosphere at RT. Themixture was stirred overnight then quenched with HCl/methanol (2 M).After the solvent was removed in vacuo, the residue was washed withwater to afford2-(4-methoxy-benzyl)-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-3-one (480 mg,54%). ¹H-NMR (CDCl₃): δ 7.36 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H),4.87 (m, 1H), 4.68 (s, 2H), 4.03 (d, J=7.2 Hz, 2H), 3.80 (s, 3H).

Example EE

To a stirred solution of chlorosulfonyl isocyanate (1.43 g, 10.0 mmol)in CH₂Cl₂ (20 mL) at 0° C. was added benzyl alcohol (1.08 g, 10.0 mmol)at such a rate that the reaction solution temperature did not rise above5° C. After stirring for 1.5 h, a solution of L-alanine methyl ester(1.45 g, 12.0 mmol) and Et₃N (3.2 mL, 25.0 mmol) in CH₂Cl₂ (20 mL) wasadded at such a rate that the reaction temperature didn't rise above 5°C. When the addition was completed, the reaction solution was allowed towarm up to RT and stirred overnight. The reaction mixture was pouredinto 10% HCl, extracted with CH₂Cl₂, the organic extracts washed withsaturated NaCl, dried (Mg₂SO₄), and filtered. After removal of thesolvent, the crude product was recrystallized in PE/EA (10:1) to affordthe desired product (2.5 g, 79%), which was used directly in the nextstep. ¹H-NMR (DMSO): δ 11.31 (s, 1H), 8.43 (d, J=8.0 Hz, 1H), 7.37-7.32(m, 5H), 5.11 (s, 2H), 4.03 (m, 1H), 3.57 (s, 3H), 1.23 (d, J=7.2 Hz,3H).

A mixture of material from the previous reaction (2.5 g, 12 mmol) andPd/C (10%, 250 mg) in methanol was stirred for 4 h at 50° C. under H₂atmosphere (55 psi). After the catalyst was removed by suction, thefiltrate was evaporated to afford the desired compound (1.37 g, 92%) asa white solid, which was used directly in the next step. ¹H-NMR (CDCl₃):δ 5.51 (d, J=5.6 Hz, 1H), 4.94 (br, 2H), 4.18 (m, 1H), 3.78 (s, 3H),1.46 (d, J=7.2 Hz, 3H).

To a solution of 2.0 N of NaOMe in methanol (20 mL) was added a solutionof compound form the previous reaction (1.2 g, 6.1 mmol) in methanol andthe resulting mixture was heated to reflux overnight. After coolingdown, a solution of HCl in methanol was added to acidify to pH 7. Theresulted salt was filtered off and the filtrate was evaporated todryness to afford a light yellow solid which was used directly in thenext step (600 mg, 66%). ¹H-NMR (DMSO-d₆): δ 6.04 (d, J=4.8 Hz, 1H),3.60 (m, 1H), 1.11 (d, J=7.2 Hz, 3H).

A mixture of compound from the previous step (500 mg, 3.33 mmol) and1-chloromethyl-4-methoxybenzene (156 mg, 1.0 mmol) in acetonitrile washeated to reflux overnight together with K₂CO₃ (207 mg, 1.5 mmol) and KI(250 mg, 1.5 mmol) under N₂ atmosphere. After cooling, the salt wasfiltered off and the filtrate was purified by column to afford2-(4-methoxybenzyl)-(S)-4-methyl-1,1-dioxo-16[1,2,5]thiadiazolidin-3-one as a white solid (200 mg), which was usedwithout further purification.

Example 160

To a solution of Example EE (100 mg, 0.37 mmol) in anhydrous DMF (3 mL)was added NaH (18 mg, 0.44 mmol) at 0° C. After stirring for 0.5 h at 0°C., a solution of Example E (160 mg, 0.37 mmol) in anhydrous DMF (3 mL)was added to the reaction mixture, which was stirred overnight at RT andsubsequently concentrated under reduced pressure to yield a crude solidwhich was used without further purification.

A solution of the crude material from the previous reaction (60 mg,0.090 mmol) in trifluoroacetic acid (3 mL) was stirred at 50° C. for 4h. After the solvent was removed, the residue was purified bypreparative HPLC to afford1-{5-t-butyl-2-[3-((S)-3-methyl-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea as white power(45 mg). ¹H NMR (DMSO-d₆): 9.04 (s, 1H), 8.87 (s, 1H), 8.02 (d, J=8.0Hz, 1H), 7.89 (d, J=7.2 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.41-7.52 (m,6H), 6.40 (s, 1H), 4.31-4.49 (dd, J=8.0 Hz, 2H), 4.03 (q, J=6.8 Hz, 1H),1.27 (s, 9H), 1.17 (d, J=8.0 Hz, 3H). MS (ESI) m/z: 547 (M+H⁺).

Example FF

2-(4-methoxy-benzyl)-(R)-4-methyl-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-3-onewas prepared from D-alanine ethyl ester using the same procedure asExample EE.

Example 161

To a solution of Example FF (60 mg, 0.22 mmol) in anhydrous DMF (2 mL)was added NaH (11 mg, 0.27 mmol) at 0° C. After stirring for 0.5 h at 0°C., a solution of Example D (100 mg, 0.22 mmol) in anhydrous DMF (2 mL)was added to the reaction mixture, which was stirred overnight at RT.The crude reaction mixture was concentrated under reduced pressure andthe residue by purified through preparative HPLC to yield1-(5-t-butyl-2-{3-[5-(4-methoxy-benzyl)-(R)-3-methyl-1,1,4-trioxo-1λ⁶-[1,2,5]-thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-naphthalene-1-yl-urea(20 mg). ¹H NMR (DMSO-d₆): 8.98 (s, 1H), 8.81 (s, 1H), 8.00 (d, J=8.0Hz, 1H), 7.90 (d, J=7.2 Hz, 2H), 7.62 (s, 2H), 7.51-7.55 (m, 6H), 7.44(d, J=7.6 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.40(s, 1H), 4.57-4.62 (dd, J=8.0 Hz, 4H), 4.53 (q, J=7.6 Hz, 1H), 3.71 (s,3H), 1.30 (d, J=8.0 Hz, 3H), 1.27 (s, 9H). MS (ESI) m/z: 653 (M+H⁺).

A solution of1-(5-t-Butyl-2-{3-[5-(4-methoxy-benzyl)-(R)-3-methyl-1,1,4-trioxo-1λ⁶-[1,2,5]-thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-naphthalen-1-yl-urea(20 mg, 0.030 mmol) in trifluoroacetic acid (2 mL) was stirred at 50° C.for 4 h. After the solvent was removed, the residue was purified bypreparative-HPLC to afford1-{5-t-butyl-2-[3-((R)-3-methyl-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-ureaas a white power (6 mg). ¹H NMR (DMSO-d₆): 8.99 (s, 1H), 8.80 (s, 1H),8.00 (d, J=7.2 Hz, 1H), 7.90 (d, J=7.2 Hz, 2H), 7.60-7.64 (m, 2H),7.44-7.54 (m, 7H), 6.41 (s, 1H), 4.31-4.49 (dd, J=8.0 Hz, 2H), 4.03 (q,J=7.6 Hz, 1H), 1.27 (s, 9H), 1.19 (d, J=8.0 Hz, 3H). MS (ESI) m/z: 533(M+H⁺).

Example 162

To a solution of Example CC (0.263 g, 1.0 mmol) in THF (2.0 mL) wasadded a solution of 1-fluoro-4-isocyanato-benzene (0.114 mL, 1.101 mmol)in THF (5.0 mL) at 0° C. The mixture was stirred at RT for 1 h thenheated until all solids were dissolved. The mixture was stirred at RTfor 3 h and poured into water (20 mL). The resulting precipitate wasfiltered, washed with diluted HCl and H₂O, dried under reduced pressureto yield1-[5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-yl]-3-(4-fluoro-phenyl)-urea(400 mg) as a white power. ¹H NMR (DMSO-d₆): 8.99 (s, 1H), 8.38 (s, 1H),7.59 (s, 1H), 7.44-7.51 (m, 3H), 7.38-7.40 (m, 2H), 7.08 (t, J=8.8 Hz,2H), 6.34 (s, 1H), 4.83 (s, 2H), 1.26 (s, 9H). MS (ESI) m/z: 401 (M+H⁺).

To a solution of2-(4-methoxy-benzyl)-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-3-one (64 mg,0.25 mmol) in anhydrous DMF (2 mL) was added NaH (11 mg, 0.27 mmol) at0° C. After stirred for 0.5 h at 0° C., a solution of1-[5-t-butyl-2-(3-chloromethyl-phenyl)-2H-pyrazol-3-yl]-3-(4-fluoro-phenyl)-ureafrom the previous reaction (100 mg, 0.25 mmol) in anhydrous DMF (2 mL)was added to the reaction mixture, then was stirred overnight at RT. Thecrude was purified through prepared-HPLC to yield1-(5-t-butyl-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-fluoro-phenyl)-urea(45 mg). ¹H NMR (DMSO-d₆): 8.95 (s, 1H), 8.37 (s, 1H), 7.50-7.54 (m,3H), 7.36-7.41 (m, 3H), 7.25 (d, J=8.8 Hz, 2H), 7.07 (t, J=8.8 Hz, 2H),6.87 (d, J=8.4 Hz, 2H), 6.35 (s, 1H), 4.64 (s, 2H), 4.47 (s, 2H), 4.19(s, 2H), 3.75 (s, 3H), 1.26 (s, 9H). MS (ESI) m/z: 515 (M+H⁺).

A solution of1-(5-t-butyl-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-fluoro-phenyl)-urea(40 mg, 0.060 mmol) in trifluoroacetic acid (3 mL) was stirred at 50° C.for 4 h. After the solvent was removed, the residue was purified bypreparative HPLC to afford1-{5-t-butyl-2-[3-(3-(R)-methyl-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-ureaas a white power (12 mg). ¹H NMR (DMSO-d₆): 8.98 (s, 1H), 8.39 (s, 1H),7.37-7.51 (m, 6H), 7.07 (t, J=8.8 Hz, 2H), 6.35 (s, 1H), 4.21 (s, 2H),3.88 (s, 2H), 1.26 (s, 9H). MS (ESI) m/z: 501 (M+H⁺).

Example GG

To a stirred suspension of K₂CO₃ (5.5 g, 40 mmol) and1-bromo-3-chloro-propane (3.78 g, 24 mmol) in acetonitrile (10 mL) wasadded a solution of N-methyl piperazine (2.0 g, 20 mmol) in acetonitrile(10 mL) dropwise at RT. After the addition was completed, the reactionmixture was stirred for 3 h then filtered. The filtrate was concentratedand dissolved in CH₂Cl₂, washed with brine, dried (NaSO₄) and filtered.After removal of the solvent, the residue was dissolved in ether. To theabove solution was added the solution of HCl and filtered to afford thedesired product (2.3 g, 65.7%). ¹H NMR (D₂O): 3.61 (t, J=6.0 Hz, 2H),3.59 (br, 8H), 3.31 (t, J=8.0 Hz, 2H), 2.92 (s, 3H), 2.15 (m, 2H).

Example 163

To a solution of Example 41 (100 mg, 0.25 mmol) in acetonitrile (10 mL)was added Example GG (75 mg, 0.30 mmol) and K₂CO₃ (172 mg, 1.25 mmol).The resulting mixture was stirred at 45° C. for 3 h before filtered.After the filtrate was concentrated, the residue was purified bypreparative TLC to afford1-(5-t-Butyl-2-{3-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-2H-pyrazol-3-yl)-3-naphthalen-1-yl-urea(31 mg, 23%). ¹H-NMR (CD₃OD): 7.93 (m, 1H), 7.88 (m, 1H), 7.71 (d, J=8.4Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.43-7.50 (m, 4H), 7.14 (m, 2H), 7.05(m, 1H), 6.43 (s, 1H), 4.10 (t, J=6.0 Hz, 2H), 3.09-3.15 (br, 4H),2.74-2.86 (br, 6H), 2.72 (s, 3H), 1.99 (t, J=6.8 Hz, 2H), 1.35 (s, 9H).MS (ESI) m/z: 541 (M+H⁺).

Example HH

Intermediate HH was synthesized according to literature proceduresstarting from 4,4-dimethyl-3-oxo-pentanenitrile (10 mmole) in absoluteethanol and HCl in quantitative afford.

Example II

Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH₂Cl₂(25 mL) and cooled in an ice bath. The suspension is stirred for 5 minand 1-napthylchloroformate is added dropwise over 5 min. The reactionmixture is stirred an additional 5 min at 0° C., and the reaction iswarned and stirred at RT for 1 h. The reaction is pour into ethylacetate (100 mL) and water (100 ml). After shaking, the aqueous layer isremoved, the organic layer washed with water, dried (MgSO₄) andconcentrated to afford (Z)-naphthalen-1-yl1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.

Example 164

Example II (10 mmol) is dissolved in absolute EtOH (50 mL) at RT andExample Y (10.5 mmol) is added dropwise over 5 min. The reaction mixtureis stirred for 30 min at RT, poured in water (100 mL) and ethyl acetate(100 mL). After shaking, the organic layer is washed with 5% HCl, water,dried (MgSO₄) and concentrated to afford 1-naphthyl1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 165

A solution of Example 164 (0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL)is stirred at RT overnight. The reaction mixture is neutralized to pH=4,extracted with ethyl acetate (3×20 mL), the combined organic extractsare washed with brine, dried (NaSO₄) and filtered. The filtrate isconcentrated to afford 1-napthyl1-(3-(2-carboxyethylphenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example JJ

Example JJ is synthesized utilizing Example HH and2-napthylchloroformate according to the procedure described for ExampleII to afford(Z)-naphthalen-2-yl-1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.

Example 166

Example 166 is synthesized utilizing Example Y and Example JJ accordingto the procedure described for Example 79 to afford 2-naphthyl1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 167

Example 167 is synthesized utilizing Example 166 according to theprocedure described for Example 165 to afford 2-napthyl1-(3-(2-carboxyethylphenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example KK

Example KK is synthesized utilizing Example HH andp-chlorophenylchloroformate according to the procedure described forExample II to afford (Z)-4-chlorophenyl1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.

Example 168

Example 168 is synthesized utilizing Example Y and Example KK accordingto the procedure described for Example 164 to afford 4-chlorophenyl1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 169

Example 169 is synthesized utilizing Example 168 according to theprocedure described for Example 165 to afford 4-chlorophenyl1-(3-(2-carboxyethylphenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example LL

Example LL is synthesized utilizing Example HH andp-methoxyphenylchloroformate according to the procedure described forExample II to afford (Z)-4-methoxyphenyl1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate.

Example 170

Example 170 is synthesized utilizing Example Y and Example LL accordingto the procedure described for Example 164 to afford 4-methoxyphenyl1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 171

Example 171 is synthesized utilizing Example 170 according to theprocedure described for Example 165 to afford 4-methoxyphenyl1-(3-(2-carboxyethylphenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example MM

Example MM is synthesized utilizing Example HH andquinolin-8-yl-chloroformate according to the procedure described forExample II to afford (Z)-quinolin-8-yl1-ethoxy-4,4-dimethyl-3-oxopentylidenecarbamate

Example 172

Example 172 is synthesized utilizing Example Y and Example MM accordingto the procedure described for Example 164 to afford quinolin-8-yl1-(3-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 173

Example 173 is synthesized utilizing Example 172 according to theprocedure described for Example 165 to afford quinolin-8-yl1-(3-(2-carboxyethylphenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 174

Example 174 is synthesized utilizing a mixture of4-methoxy-1-naphthylamine and Example Z according to the proceduredescribed for Example 147 to afford3-(3-{3-t-butyl-5-[3-(4-methoxy-1-naphthyl)-ureido]-pyrazol-1-yl}-phenyl)-propionicacid ethyl ester.

Example 175

Utilizing the same synthetic procedure as for Example 146 and startingwith Example 174,3-(3-{3-t-butyl-5-[3-(4-methoxy-1-naphthyl)-ureido]-pyrazol-1-yl}-phenyl)-propionicacid is synthesized.

Example 176

Example 176 is synthesized utilizing a mixture of indoline and Example Zaccording to the procedure described for Example 147 to afford ethyl3-(3-(3-t-butyl-5-(indoline-1-carboxamido)-1H-pyrazol-1-yl)phenyl)propanoate.

Example 177

Utilizing the same synthetic procedure as for Example 146 and startingwith Example 173,3-(3-(3-t-butyl-5-(indoline-1-carboxamido)-1H-pyrazol-1-yl)phenyl)propionic acid is synthesized.

Example NN

Utilizing the same synthetic procedure as for Example Y and startingwith p-bromo nitrobenzene, 3-(4-hydrazino-phenyl)-propionic acid ethylester is synthesized.

Example 178

Utilizing the same synthetic procedure as for Example 164, Example II(10 mmol) and Example NN (10.5 mmol) are combined to afford 1-naphthyl1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 179

Example 179 is synthesized utilizing Example 178 according to theprocedure described for Example 165 to afford 1-napthyl1-(4-(2-carboxyethylphenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 180

Utilizing the same synthetic procedure as for Example 164, Example JJ(10 mmol) and Example NN (10.5 mmol) are combined to afford 2-naphthyl1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 181

Example 181 is synthesized utilizing Example 180 according to theprocedure described for Example 165 to afford 2-napthyl1-(4-(2-carboxyethylphenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 182

Utilizing the same synthetic procedure as for Example 164, Example KK(10 mmol) and Example NN (10.5 mmol) are combined to affordp-chlorophenyl1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 183

Example 183 is synthesized utilizing Example 182 according to theprocedure described for Example 165 to afford 4-chlorophenyl1-(4-(2-carboxyethylphenyl)-3-t-butyl-1 H-pyrazol-5-ylcarbamate.

Example 184

Utilizing the same synthetic procedure as for Example 164, Example LL(10 mmol) and Example NN (10.5 mmol) are combined to affordp-methoxyphenyl1-(4-(2-(ethoxycarbonyl)ethyl)phenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example 185

Example 185 is synthesized utilizing Example 184 according to theprocedure described for Example 165 to afford p-methoxyphenyl1-(4-(2-carboxyethylphenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate.

Example OO

Ethyl bromoacetate is reacted with meta-nitrophenol under standardconditions to afford ethyl 2-(3-nitrophenoxy)acetate, which iselaborated to ethyl 2-(3-hydrazinophenoxy)acetate using thereduction/oxidation sequence described for Example Y.

Example PP

Example HH and 1-naphthylisocyanate are combined utilizing the samesynthetic procedure as for Example II to afford(Z)-1-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)-3-(naphthalen-1-yl)urea.

Example 186

Utilizing the same synthetic procedure as for Example 164, Example PP(10 mmol) and Example OO (10.5 mmol) are combined to afford3-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-1-yl}-phenoxy)-aceticacid ethyl ester.

Example 187

Utilizing the same synthetic procedure as for Example 146 and startingwith Example 186,3-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-1-yl}-phenoxy)-aceticacid is synthesized.

Example QQ

Example HH and 4-chlorophenylisocyanate are combined utilizing the samesynthetic procedure as for Example II to afford(Z)-1-(4-chlorophenyl)-3-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)urea

Example 188

Utilizing the same synthetic procedure as for Example 164, Example QQ(10 mmol) and Example OO (10.5 mmol) are combined to afford3-(3-{3-t-butyl-5-[3-(1-4-chlorophenyl)-ureido]-pyrazol-1-yl}-phenoxy)-aceticacid ethyl ester.

Example 189

Utilizing the same synthetic procedure as for Example 146 and startingwith Example 188,3-(3-{3-t-butyl-5-[3-(14-chlorophenyl)-ureido]-pyrazol-1-yl}-phenoxy)-aceticacid is synthesized.

Example RR

Ethyl bromoacetate is reacted with para-nitrophenol under standardconditions to afford ethyl 2-(4-nitrophenoxy)acetate, which iselaborated to ethyl 2-(4-hydrazinophenoxy)acetate using thereduction/oxidation sequence described for Example Y.

Example 190

Utilizing the same synthetic procedure as for Example 164, Example PP(10 mmol) and Example RR (10.5 mmol) are combined to afford4-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-1-yl}-phenoxy)-aceticacid ethyl ester.

Example 191

Utilizing the same synthetic procedure as for Example 146 and startingwith Example 190,4-(3-{3-t-butyl-5-[3-(1-naphthyl)-ureido]-pyrazol-1-yl}-phenoxy)-aceticacid is synthesized.

Example 192

Utilizing the same synthetic procedure as for Example 164, Example QQ(10 mmol) and Example RR (10.5 mmol) are combined to afford4-(3-{3-t-butyl-5-[3-(1-4-chlorophenyl)-ureido]-pyrazol-1-yl}-phenoxy)-aceticacid ethyl ester.

Example 193

Utilizing the same synthetic procedure as for Example 146 and startingwith Example 192,4-(3-{3-t-butyl-5-[3-(14-chlorophenyl)-ureido]-pyrazol-1-yl}-phenoxy)-aceticacid is synthesized.

Example DD

To a stirred solution of chlorosulfonyl isocyanate (1.43 g, 10.0 mmol)in CH₂Cl₂ (20 mL) at 0° C. was added 2-methyl-propan-2-ol (0.74 g, 10.0mmol) at such a rate that the reaction solution temperature did not riseabove 5° C. After being stirred for 1.5 h, a solution of glycine ethylester (1.45 g, 12.0 mmol) and Et₃N (3.2 mL, 25.0 mmol) in CH₂Cl₂ (20 mL)was added at such a rate that the reaction temperature didn't rise above5° C. When the addition was completed, the solution was warmed to RT andstirred overnight. The reaction mixture was poured into 10% HCl andextracted with CH₂Cl₂. The organic layer was washed with saturated NaCl,dried (Mg₂SO₄) and filtered. After removal of the solvent, the crudeproduct was washed with CH₂Cl₂ to afford ethyl2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate (2.4 g, 85%). ¹H-NMR(DMSO): δ 10.85 (s, 1H), 8.04 (t, J=6.0 Hz, 1H), 4.07 (q, J=5.6 Hz, 2H),3.77 (d, J=6.0 Hz, 2H), 1.40 (s, 9H), 1.18 (t, J=7.2 Hz, 3H).

To a solution of methanol (8.5 mmol) and triphenylphosphine (2.6 g, 8.5mol) in dry THF is added a solution of ethyl2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previous step(2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at 0° C.under N₂ atmosphere. The mixture is stirred at 0° C. for 2 h, warmed toRT and is stirred overnight. After the solvent is removed in vacuo, theresidue is purified by column chromatography to afford ethyl2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate.

To a solution of HCl in methanol (2 M) is added ethyl2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate from theprevious step (5.0 mmol) in portions at RT and the mixture is stirredfor 3 h. After the solvent is removed in vacuo, the residue is washedwith diethyl ether to afford ethyl 2-((N-methylsulfamoyl)amino)acetate

To a solution of ethyl 2-((N-methylsulfamoyl)amino)acetate from theprevious step (3.5 mmol) in DMF (50 mL) is added KO-t-Bu (1.56 g, 13.88mmol) in portions under N₂ at RT. The mixture is stirred overnight thenquenched with HCl/methanol (2 M). After the solvent is removed in vacuo,the residue is washed with water to afford2-methyl-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-3-one (480 mg, 54%). ¹H-NMR(CDCl₃): δ 7.36 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.87 (m, 1H),4.68 (s, 2H), 4.03 (d, J=7.2 Hz, 2H), 3.80 (s, 3H).

Example 194

Example E and Example OO are combined utilizing the procedure forExample 160 to afford1-(5-t-butyl-2-{3-[5-methyl-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-naphthyl-urea.

Example 195

To a solution of Example X (2.9 g, 10 mmol) in THF (50 mL) was added asolution of 1-naphthyl isocyanate (1.7 g, 10 mmol) in THF (20 mL) at 0°C. The mixture was stirred at RT for 1 h and heated until all solidsdissolved. The mixture was then stirred at RT for 3 h and poured intowater (200 mL). The precipitate was filtered, washed with diluted HCland H₂O, dried under vacuum to give 4.3 g of4-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]-benzoic acidethyl ester, which was used without further purification.

Example 196

To a solution of Example B (228 mg, 0.5 mmol) in dry THF (20 mL) wasadded dropwise a solution of methyl magnesium bromide in toluene/THF(3.6 mL, 5.0 mmol) at −78° C. under N₂. After stirring for 1 h, themixture was allowed to rise to RT and stirred for another 2 h. Thereaction mixture was quenched with saturated NH₄Cl solution and aqueousHCl solution (10%), extracted with ethyl acetate. The combined organicextracts were washed with brine, dried (Na₂SO₄), the solvent removed invacuo and the residue purified by column chromatography to afford1-{5-t-butyl-2-[3-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea(150 mg, 67%). ¹H NMR (DMSO-d6): 9.00 (s, 1H), 8.75 (s, 1H), 7.98 (d,J=7.6 Hz, 1H), 7.92-7.89 (m, 2H), 7.65-7.62 (m, 2H), 7.52-7.44 (m, 5H),7.37 (d, J=6.8 Hz, 1H), 6.39 (s, 1H), 5.13 (s, 1 H), 1.45 (s, 6H), 1.27(s, 9H); MS (ESI) m/z: 443 (M+H⁺).

Example 197

To a solution of Example C (220 mg, 0.5 mmol) in dry THF (20 mL) wasadded dropwise a solution of methyl magnesium bromide in toluene/THF(3.6 mL, 5.0 mmol) at −78° C. under N₂. After stirring for 1 h, themixture was allowed to rise to RT and stirred for another 2 h. Thereaction mixture was quenched with saturated NH₄Cl and aqueous HClsolution (10%), and extracted with ethyl acetate. The combined organicextracts were washed with brine, dried (Na₂SO₄), the solvent was removedin vacuo and the residue was purified by column chromatography to afford1-{5-t-butyl-2-[3-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea(174 mg, 81%). ¹H NMR (DMSO-d₆): 9.11 (s, 1H), 8.34 (s, 1H), 7.59 (s,1H), 7.46 (t, J=8.8 Hz, 1H), 7.43-7.40 (m, 3H), 7.31-7.28 (m, 3H), 6.34(s, 1H), 5.13 (s, 1H), 1.42 (s, 6H), 1.27 (s, 9H); MS (ESI) m/z: 428(M+H⁺).

Example 198

To a solution of Example 195 (228 mg, 0.5 mmol) in dry THF (20 mL) wasadded dropwise a solution of methylmagnesium bromide in toluene/THF (3.6mL, 5.0 mmol) at −78° C. under N₂. After stirring for 1 h, the mixturewas allowed to rise to RT and stirred for another 2 h. The reactionmixture was quenched with saturated NH₄Cl and aqueous HCl solution(10%), extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried Na₂SO₄), the solvent was removed in vacuo andthe residue purified by column chromatography to afford1-{5-t-butyl-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea(180 mg, 81%). ¹H NMR (DMSO-d6): 9.06 (s, 1H), 8.83 (s, 1H), 7.99 (d,J=8.0 Hz, 1H), 7.92 (t, J=8.0 Hz, 2H), 7.64-7.61 (m, 3H), 7.55-7.43 (m,5H), 6.40 (s, 1H), 5.13 (s, 1H), 1.47 (s, 6H), 1.27 (s, 9H); MS (ESI)m/z: 443 (M+H⁺).

Example 199

To a solution of Example 57 (220 mg, 0.5 mmol) in dry THF (20 mL) wasadded dropwise a solution of methyl magnesium bromide in toluene/THF(3.6 mL, 5.0 mmol) at −78° C. under N₂. After stirring for 1 h, themixture was allowed to rise to RT and stirred for another 2 h. Thereaction mixture was quenched with saturated NH₄Cl and aqueous HClsolution (10%), and extracted with ethyl acetate. The combined organicextracts were washed with brine, dried (Na₂SO₄), the solvent removed invacuo and the residue was purified by column chromatography to afford1-{5-t-butyl-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea(187 mg, 87%). ¹H-NMR (CDCl₃): 9.14 (s, 1H), 8.42 (s, 1H), 7.58 (d,J=8.4 Hz, 2H), 7.42 (d, J=5.6 Hz, 2H), 7.40 (d, J=4.8 Hz, 2H), 7.29 (d,J=8.8 Hz, H), 6.34 (s, 1H), 5.11 (s, 1H), 1.44 (s, 6H), 1.25 (s, 9H); MS(ESI) m/z: 427 (M+H⁺).

Example PP

To a solution of 3-bromo-phenylamine (17 g, 0.1 mol) in concentrated HCl(200 mL) was added an aqueous solution (20 mL) of NaNO₂ (7 g, 0.1 mol)at 0° C. and the resulting mixture was stirred for 1 h. A solution ofSnCl₂.2H₂O (45 g, 0.2 mmol) in concentrated HCl (500 mL) was then addedat 0° C. The reaction solution was stirred for an additional 2 h at RT.The precipitate was filtered and washed with ethanol and ether to give(3-bromo-phenyl)-hydrazine as a white solid, which was used for the nextreaction without further purification

Example QQ

A mixture of Example PP (22.2 g, 0.1 mol) and4,4-dimethyl-3-oxo-pentanenitrile (18.7 g, 0.15 mol) in ethanol (250 mL)was heated to reflux overnight. The reaction solution was concentratedunder reduced pressure, and the residue purified by columnchromatography to afford2-(3-bromo-phenyl)-5-t-butyl-2H-pyrazol-3-ylamine as a white solid. ¹HNMR (DMSO-d₆): 7.85 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.2 Hz,1H), 7.50 (t, J=8.0 Hz, 1H), 5.62 (s, 1H), 1.27 (s, 9H).

Example RR

To a mixture of Example QQ (2.94 g, 10 mmol), Pd(OAc)₂ (1 mmol), PPh₃(20 mmol), and K₂CO₃ (20 mmol) in MeCN (50 mL) was added2-methyl-acrylic acid ethyl ester (20 mmol). The resulting mixture washeated to reflux overnight, filtered, concentrated, and the residue waspurified by column chromatography to afford 1.2 g of3-[3-(5-Amino-3-t-butyl-pyrazol-1-yl)-phenyl]-2-methyl-acrylic acidethyl ester. ¹H NMR (CDCl₃): 7.41 (s, 1H), 7.40-7.36 (m, 2H), 7.15 (d,J=6.8 Hz, 1H), 6.24 (s, 1H), 5.51 (s, 1H), 4.27 (q, J=7.2 Hz, 2H), 2.12(s, 3H), 1.33 (s, 9H), 1.27 (t, J=7.2 Hz, 3H).

Example SS

A mixture of Example RR (1.2 g,) and Pd/C (120 mg, 10%) in methanol (50mL) was stirred under 40 psi of H₂ at RT overnight, filtered. Andconcentrated to afford3-[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-2-methyl-propionic acidethyl ester as a racemate (1.1 g), which was used for the next reactionwithout further purification.

Example 200

To a solution of Example SS (100 mg, 0.3 mmol) and Et₃N (60 mg, 0.6mmol) in CH₂Cl₂ (10 mL) was added 1-isocyanato-naphthalene (77 mg, 0.45mmol). The resulting mixture was stirred at RT overnight, added to water(50 mL), extracted with CH₂Cl₂ (3×30 mL) and the combined organicextracted were washed with brine, dried (Na₂SO₄), and filtered. Afterconcentration under reduced pressure, the residue was purified bypreparative-TLC to afford3-(3-{3-t-butyl-5-[3-(4-fluoro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionicacid ethyl ester as a racemate (50 mg, 33%). ¹H-NMR (CDCl₃): 7.99 (s,1H), 7.91 (d, J=8.4 Hz, 1H), 7.84 (t, J=7.2 Hz, 2H), 7.67 (d, J=8.4 Hz,1H), 7.49-7.41 (m, 3H), 7.35-7.33 (m, 3H), 7.21 (s, 1H), 7.14-7.13 (m,1H), 6.65 (s, 1H), 3.98 (q, J=6.0 Hz, 2H), 2.92-2.88 (m, 3H), 1.36 (s,9H), 1.24 (d, J=6.0 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 499(M+H⁺).

Example 201

A solution of Example 200 (17 mg, mmol) and 2N LiOH (3 mL) in MeOH (3mL) was stirred at RT over night. The reaction mixture was adjusted topH=4, and extracted with ethyl acetate (3×20 mL). The combined organicextracts were washed with brine, dried (Na₂SO₄), and filtered. After thefiltrate was concentrated, the residue was purified by preparative-TLCto afford3-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]-phenyl}-2-methyl-propionicacid as a racemate (15 mg, 92%). ¹H NMR (DMSO): 11.81 (br s, 1H), 9.58(s, 1H), 8.56 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H),7.55 (d, J=7.6 Hz, 1H), 7.45-7.35 (m, 5H), 7.28 (d, J=8.0 Hz, 1H), 7.14(t, J=7.6 Hz, 1H), 6.52 (s, 1H), 3.77 (m, 1H), 2.65 (m, 1H), 2.36 (m,1H), 1.27 (s, 9H), 1.00 (d, J=6.8 Hz, 3H); MS (ESI) m/z: 471 (M+H⁺).

Example 202

To a solution of Example SS (100 mg, 0.3 mmol) and Et₃N (60 mg, 0.6mmol) in CH₂Cl₂ (10 mL) was added 1-chloro-4-isocyanato-benzene (77 mg,0.45 mmol). The resulting mixture was stirred at RT overnight, and thenadded to water (50 mL). The solution was extracted with CH₂Cl₂ (3×30 mL)and the combined organic extracts were washed with brine, dried(Na₂SO₄), and filtered. After concentration under reduced pressure, theresidue was purified by preparative-TLC to afford3-(3-{3-t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-2-methyl-propionicacid ethyl ester as a racemate (51 mg, 35%). ¹H-NMR (CDCl₃): 8.20 (s,1H), 7.39 (d, J=4.4 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.21 (t, J=8.4 Hz,2H), 7.14-7.11 (m, 2H), 6.59 (s, 1H), 4.04-3.99 (m, 2H), 3.00 (m, 1H),2.93 (m, 1H), 2.83 (m, 1H), 1.34 (s, 9H), 1.17 (d, J=6.4 Hz, 3H), 1.15(t, J=7.2 Hz, 3H); MS (ESI) m/z: 483 (M+H⁺).

Example 203

A solution of Example 202 (15 mg, mmol) and 2N LiOH (3 mL) in MeOH (3mL) was stirred at RT overnight. The reaction mixture was adjusted topH=4, extracted with ethyl acetate (3×20 mL), the combined organicextracts were washed with brine, dried (Na₂SO₄), and filtered. After thefiltrate was concentrated, the residue was purified by preparative-TLCto afford3-(3-{3-t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-2-methyl-propionicacid as a racemate (13 mg, 90%). ¹H NMR (DMSO): 12.48 (br s, 1H), 9.35(br s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.34-7.32 (m, 2H), 7.26 (d, J=8.4Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.10 (d, J=7.6 Hz, 1H), 6.45 (s, 1H),2.74 (m, 1H), 2.65 (m, 1H), 2.31 (m, 2H), 1.26 (s, 9H), 0.99 (d, J=6.8Hz, 3H); MS (ESI) m/z: 455 (M+H⁺).

Example 204

To a stirred solution of Example 195 (500 mg, 0.83 mmol) in THF (10 mL)was added LiAlH₄ powder (65 mg, 1.66 mmol) in portion at 0° C. under N₂.The mixture was stirred for 2 h at RT, excess LiAlH₄ was destroyed by aslow addition of ice, and the reaction mixture was acidified to pH=7with dilute HCl. After the solvent was removed, the residue wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried (Na₂SO₄), and filtered. After concentration in vacuo,the crude product was purified by preparative-TLC to afford1-[2-(4-hydroxymethyl-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea(415 mg, 92%). ¹H NMR (DMSO-d₆): 9.04 (s, 1H), 8.78 (s, 1H), 7.98 (d,J=8.0 Hz, 1H), 7.90 (d, J=7.2 Hz, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.55-7.42(m, 7H), 6.39 (s, 1H), 5.30 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H),1.27 (s, 9H); MS (ESI) m/z: 415 (M+H).

Example 205

To a solution of Example 204 (200 mg) in CH₂Cl₂ (50 mL) was added MnO₂(450 mg) at RT. The suspension was stirred for 2 h then filtered throughcelite. The filtrate was concentrated under reduced pressure to afford150 mg of1-[5-t-butyl-2-(4-formyl-phenyl)-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea,which was used without further purification.

Example 206

To a solution of (trifluoromethyl)trimethylsilane (77 mg) and TBAF (10mg) in THF (10 mL) was added Example 205 (150 mg) in THF (10 mL) underN₂ atmosphere in ice-bath. The resulting mixture was stirred at 0° C.for 1 h and then warmed to RT for an additional hour. To the reactionwas then added 0.5 mL of 3 NHCL, which was then stirred at RT overnight.After removal the solvent, the residue was dissolved in CH₂Cl₂ (50 mL).The organic layer was washed with saturated NaHCO₃ and brine, dried(Na₂SO₄), and filtered. After the filtrate was concentrated underreduced pressure, the residue was purified by preparative-TLC to affordthe final product1-{5-t-Butyl-2-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea(110 mg, 63%). ¹H NMR (DMSO-d₆): 9.07 (s, 1H), 8.89 (s, 1H), 8.03 (d,J=8.0 Hz, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.67-7.62 (m, 5H), 7.55-7.51 (m,2H), 7.44 (t, J=8.0 Hz, 1H), 6.95 (d, J=6.0 Hz, 1H), 6.42 (s, 1H), 5.27(m, 1H), 1.28 (s, 9H). MS (ESI) m/z: 483 (M+H⁺).

Example 207

To a stirred solution of Example 57 (500 mg, 1.1 mmol) in THF (10 mL)was added LiAlH₄ powder (65 mg, 1.66 mmol) in portion at 0° C. under N₂.The mixture was stirred for 2 h at RT, excess LiAlH₄ was destroyed by aslow addition of ice, and the reaction mixture was acidified to pH=7with diluted HCl. After the solvent removal, the residue was extractedwith ethyl acetate, and the combined organic extracts were washed withbrine, d dried (Na₂SO₄), and filtered, After solvent removal, the crudeproduct was purified by preparative TLC to1-[5-t-butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-(4-chloro-phenyl)-urea(380 mg, 92%) as a white powder. ¹H-NMR (CDCl₃): 8.17 (br s, 1H), 7.22(s, 4H), 7.17 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 7.04 (s, H),6.38 (s, 1H), 4.51 (s, 1H), 1.22 (s, 9H); MS (ESI) m/z: 399 (M+H⁺).

Example 208

To a solution of Example 207 (200 mg) in CH₂Cl₂ (50 mL) was added MnO₂(450 mg) at RT. The suspension was stirred for 2 h, then filteredthrough celite. The filtrate was concentrated to afford 160 mg of1-[5-t-butyl-2-(4-formyl-phenyl)-2H-pyrazol-3-yl]-3-(4-chloro-phenyl)-urea,which was used without further purification.

Example 209

To a solution of (trifluoromethyl)trimethylsilane (86 mg) and TBAF (10mg) in THF (10 mL) was added Example 208 (160 mg) in THF (20 mL) underN₂ atmosphere in ice-bath. The resulting mixture was stirred at 0° C.for 1 h and then warmed to RT for an additional hour. To the reactionwas added 0.5 mL of 3 N HCl, which was then stirred at RT overnight.After removal of the solvent, the residue was dissolved in CH₂Cl₂ (100mL). The organic extracts were washed with saturated NaHCO₃ and brine,dried (Na₂SO₄), and filtered. After the filtrate was concentrated underreduced pressure, the residue was purified by preparative-TLC to affordthe final product1-{5-t-butyl-2-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-2H-pyrazol-3-yl}-3-(4-chloro-phenyl)-urea(120 mg, 64%). ¹H-NMR (DMSO-d₆): 9.15 (s, 1H), 8.50 (s, 1H), 7.61 (d,J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 7.28 (d,J=8.8 Hz, 2H), 6.91 (d, J=5.6 Hz, 1H), 6.36 (s, 1H), 5.25 (m, 1H), 1.26(s, 9H); MS (ESI) m/z: 467 (M+H⁺).

Example 210

A solution of Example 151 (42 mg, 0.1 nmol) and 2N LiOH (3 mL) in MeOH(3 mL) was stirred at RT over night. The reaction mixture wasneutralized to pH=4, and extracted with ethyl acetate (3×20 mL). Thecombined organic extracts were washed with brine, dried (Na₂SO₄), andfiltered. The filtrate was concentrated to afford3-(3-{3-t-butyl-5-[(pyridine-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionicacid (30 mg, 76%). 8.45 (d, 4.0 Hz, 1H), 8.24 (d, 8.0 Hz, 1H), 7.92 (s,1H), 7.88 (t, 7.6 Hz, 1H), 7.67 (d, 8.0 Hz, 1H), 7.36 (t, 5.6 Hz, 1H),7.23 (t, 7.6 Hz, 1H), 6.96 (d, 6.8 Hz, 1H), 6.67 (s, 1H), 2.77 (t, 7.6Hz, 2H), 2.22 (t, 7.6 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 393 (M+H⁺).

Example 211

Example I is reacted with CDI and N-methyl piperazine using theprocedure for Example 145 to afford the title compound.

Example 212

Example J is reacted with CDI and N-methyl piperazine using theprocedure for Example 145 to afford the title compound.

Example 213

Example I is reacted with CDI and piperidine using the procedure forExample 145 to afford the title compound.

Example 214

Example I is reacted with CDI and morpholine using the procedure forExample 145 to afford the title compound.

Example 215

Example I is reacted with CDI and pyrrolidine using the procedure forExample 145 to afford the title compound.

Example 216

Example I is reacted with CDI and dimethylamine using the procedure forExample 145 to afford the title compound.

Example 217

Example J is reacted with CDI and piperidine using the procedure forExample 145 to afford the title compound.

Example 218

Example J is reacted with CDI and morpholine using the procedure forExample 145 to afford the title compound.

Example 219

Example J is reacted with CDI and pyrrolidine using the procedure forExample 145 to afford the title compound.

Example 220

Example J is reacted with CDI and dimethylamine using the procedure forExample 145 to afford the title compound.

Example 221

Isoquinoline-8-carboxylic acid and Example Z are reacted using theprocedure for Example 149 to afford ethyl3-(3-(3-t-butyl-5-(quinoline-8-carboxamido)-1H-pyrazol-1-yl)phenyl)propanoate.

Example 222

Example 222 is reacted using the procedure for Example 150 to afford3-(3-(3-t-butyl-5-(quinoline-8-carboxamido)-1H-pyrazol-1-yl)phenyl)propanoicacid.

Example 223

Example E is reacted with(1-ethoxy-2-methylprop-1-enyloxy)trimethylsilane under literatureconditions to afford ethyl2-(3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)benzyl)-2-methylpropanoate.

Example 224

Example 224 is reacted using the procedure for Example 150 to afford2-(3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)benzyl)-2-methylpropanoicacid

Example 225

Example G is reacted with(1-ethoxy-2-methylprop-1-enyloxy)trimethylsilane under literatureconditions to afford ethyl2-(3-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)benzyl)-2-methylpropanoate.

Example 226

Example 226 is reacted using the procedure for Example 150 to afford2-(3-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)benzyl)-2-methylpropanoicacid.

Example TT

Example 204 is reacted using the procedure for Example E to afford1-(3-t-butyl-1-(4-(chloromethyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea

Example UU

Example 122 is reacted using the procedure for Example G to afford1-(3-t-butyl-1-(4-(chloromethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.

Example 227

Example TT is reacted with(1-ethoxy-2-methylprop-1-enyloxy)trimethylsilane under literatureconditions to afford ethyl2-(4-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)benzyl)-2-methylpropanoate.

Example 228

Example 227 is reacted using the procedure for Example 150 to afford2-(4-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)benzyl)-2-methylpropanoicacid.

Example 229

Example UU is reacted with(1-ethoxy-2-methylprop-1-enyloxy)trimethylsilane under literatureconditions to afford ethyl2-(4-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)benzyl)-2-methylpropanoate

Example 230

Example 144 is reacted using the procedure for Example 150 to afford2-(4-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)benzyl)-2-methylpropanoicacid.

Example VV

N-methyl piperazine and 1-bromo-2-chloroethane are reacted using theprocedure for Example OO to afford 1-(2-chloroethyl)-4-methylpiperazinehydrochloride.

Example WW

Morpholine and 1-bromo-2-chloroethane are reacted using the procedurefor Example OO to afford 4-(2-chloroethyl)morpholine

Example XX

Morpholine and 1-bromo-3-chloropropane are reacted using the procedurefor Example OO to afford 4-(3-chloropropyl)morpholine.

Example YY

4-methylpiperidin-4-ol (made via literature methods) and1-bromo-2-chloroethane are reacted using the procedure for Example OO toafford 1-(2-chloroethyl)-4-methylpiperidin-4-ol.

Example ZZ

4-methylpiperidin-4-ol (made via literature methods) and1-bromo-3-chloropropane are reacted using the procedure for Example OOto afford 1-(3-chloropropyl)-4-methylpiperidin-4-ol.

Example AAA

A solution of 4,4-dioxothiomorpholine and 1-bromo-2-chloroethane arereacted using the procedure for Example OO to afford4-(2-chloroethyl)-4,4-dioxo-4-thiomorpholine.

Example BBB

A solution of 4,4-dioxothiomorpholine and 1-bromo-3-chloropropane arereacted using the procedure for Example OO to afford4-(3-chloropropyl)-4,4-dioxo-4-thiomorpholine.

Example CCC

A solution of 4-(trifluoromethyl)piperidin-4-ol and1-bromo-2-chloroethane are reacted using the procedure for Example 00 toafford 1-(2-chloroethyl)-4-(trifluoromethyl)piperidin-4-ol.

Example DDD

A solution of 4-(trifluoromethyl)piperidin-4-ol and1-bromo-3-chloropropane are reacted using the procedure for Example OOto afford 1-(3-chloropropyl)-4-(trifluoromethyl)piperidin-4-ol.

Example 231

Example 41 and Example WW are reacted according to the procedure forExample 194 to afford1-(1-(3-(2-morpholinoethoxy)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 232

Example 41 and Example XX are reacted according to the procedure forExample 194 to afford1-(1-(3-(3-morpholinopropoxy)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 233

Example 41 and Example VV are reacted according to the procedure forExample 194 to afford1-(1-(3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 234

Example CC, 2-naphthoic acid chloride and Example DD were combinedutilizing the same general approach for Example 162 to yieldN-(3-tert-butyl-1-(3-([5-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl]phenyl)-1H-pyrazol-5-yl)-2-naphthamide.¹H-NMR (DMSO-d₆): 10.50 (s, 1H), 8.45 (s, 1H), 8.15-8.05 (m, 3H), 7.90(s, 1H), 7.60 (t, J=7.2 Hz, 3H), 7.45 (s, 1H), 7.38 (t, J=8.0 Hz, 1H),7.27 (d, J=7.2 Hz, 1H), 6.44 (s, 1H), 4.05 (s, 2H), 1.31 (s, 9H). MS(ESI) m/z: 518 (M+H⁺).

Example 235

Example 41 and Example AAA are reacted according to the procedure forExample 194 to afford1-(1-(3-(2-(4,4-dioxo-4-thio-morpholino)ethoxy)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 236

Example 41 and Example BBB are reacted according to the procedure forExample 194 to afford1-(1-(3-(2-(4,4-dioxo-4-thio-morpholino)propoxy)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 237

Example 41 and Example YY are reacted according to the procedure forExample 194 to afford1-(1-(3-(2-(4-methylpiperidin-4-ol)ethoxy)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 238

Example 41 and Example ZZ are reacted according to the procedure forExample 194 to afford1-(1-(3-(3-(4-methylpiperidin-4-ol-)propoxy)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 239

Example 41 and Example CCC are reacted according to the procedure forExample 194 to afford1-(1-(3-(2-(4-(trifluoromethyl)piperidin-4-ol)ethoxy)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 240

Example 41 and Example DDD are reacted according to the procedure forExample 194 to afford1-(1-(3-(3-(4-(trifluoromethyl)piperidin-4-ol)propoxy)phenyl)-3-t-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 241

Example D is reacted using the procedure for Example 205 to afford1-(3-t-butyl-1-(3-formylphenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 242

Example 242 is reacted using the procedure for Example 206 to afford1-(3-t-butyl-1-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 243

Example F is reacted using the procedure for Example 208 to afford1-(3-t-butyl-1-(3-formylphenyl)-1H-pyrazol-5-yl)-3 (4-chlorophenyl)urea.

Example 244

Example 244 is reacted using the procedure for Example 209 to afford1-(3-t-butyl-1-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea

Example 245

Example B is saponified using the procedure for Example 150. Theresulting acid is reacted with trifluorotriazine in pyridine to affordthe acid fluoride which is directly reacted with CsF and TBAF accordingto literature procedures (see J. Org. Chem. USSR (Engl. Transl.), 11,1975, 315-317) to afford1-(3-t-butyl-1-(3-(difluoro(hydroxy)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 246

Example C is reacted according to the procedure for Example 245 toafford1-(3-t-butyl-1-(3-(difluoro(hydroxy)methyl)phenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.

Example 247

Example 205 is reacted according to the procedure for Example 245 toafford1-(3-t-butyl-1-(4-(difluoro(hydroxy)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 248

Example 57 is reacted according to the procedure for Example 245 toafford1-(3-t-butyl-1-(4-(difluoro(hydroxy)methyl)phenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.

Example EEE

Example EEE (tert-butyl7-hydrazinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate) was synthesizedaccording to literature procedures.

Example 249

Utilizing the same synthetic procedure as for Example 164, Example EEE(10 mmol) and Example PP (10.5 mmol) are combined to afford t-butyl7-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

Example 250

Utilizing the same synthetic procedure as for Example 164, Example EEE(10 mmol) and Example QQ (10.5 mmol) are combined to afford t-butyl7-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Example 251

Example 249 is reacted with trifluoroacetic acid under standardconditions to afford1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 252

Example 250 is reacted with trifluoroacetic acid under standardconditions to afford1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.

Example 253

Example 251 is reacted with chlorosulfonyl isocyanate then dimethylamineaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[1-N-[[(1-dimethylaminolsulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 254

Example 252 is reacted with chlorosulfonyl isocyanate then dimethylamineaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[1-N-[[(1-dimethylaminolsulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.

Example 255

Example 252, CDI, and methanesulfonamide are reacted under standardconditions to yield1-(3-t-butyl-1-[[1-N-[[(methanesulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.

Example 256

Example 251, CDI, and methanesulfonamide are reacted under standardconditions to yield1-(3-t-butyl-1-[[1-N-[[(methanesulphonyl)amino]carbonyl]-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(1-naphthyl)urea.

Example FFF

Commercially available 3-nitrobenzoic acid is reacted with methylamineand EDC under standard conditions to afford N-methyl-3-nitrobenzamide,which is reduced with LAH under standard conditions to affordN-methyl(3-nitrophenyl)methanamine, which is protected withbenzylchloroformate under standard conditions to yield t-butyl3-nitrobenzylmethylcarbamate. This material is nitrosated and reduced toyield t-butyl 3-hydrazinobenzylmethylcarbamate.

Example 257

Utilizing the same synthetic procedure as for Example 164, Example FFF(10 mmol) and Example PP (10.5 mmol) are combined to afford t-butyl3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)benzylmethylcarbamate.

Example 258

Example 257 is deprotected with trifluoroacetic acid under standardconditions to afford1-(3-t-butyl-1-(3-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 259

Example 258 is reacted with chlorosulfonyl isocyanate then piperidineaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-piperidinylsulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 260

Example 258 is reacted with chlorosulfonyl isocyanate then morpholineaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-morpholinyl-sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 261

Example 258 is reacted with chlorosulfonyl isocyanate then pyrrolidineaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-piperidinyl-sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 262

Example 258 is reacted with chlorosulfonyl isocyanate then dimethylamineaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-dimethylamino-sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 263

Example 258 is reacted with chlorosulfonyl isocyanate then ammoniaaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-aminosulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 264

Example 258 is reacted with chlorosulfonyl isocyanate then N-methylpiperazine according to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-(N-methylpiperazinyl)sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 265

Example 258 is reacted with chlorosulfonyl isocyanate then4,4-dioxo-4-thiomorpholine according to the procedure for Example 7 toafford1-(3-t-butyl-1-[[3-[[(1-(4,4-dioxo-4-thiomorpholinyl)sulphonyl)amino]carbonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 266

Chlorosulfonyl isocyanate, piperidine, then Example 258 are reactedaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-piperidinylcarbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 267

Chlorosulfonyl isocyanate, morpholine and then Example 258 are reactedaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-morpholinyl-carbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 268

Chlorosulfonyl isocyanate, pyrrolidine and then Example 258 are reactedaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-piperidinyl-carbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 269

Chlorosulfonyl isocyanate, dimethylamine, then Example 258 are reactedaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-dimethylamino-carbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 270

Chlorosulfonyl isocyanate, ammonia and then Example 258 are reactedaccording to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-aminocarbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 271

Chlorosulfonyl isocyanate, N-methyl piperazine and then Example 258 arereacted according to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-(N-methylpiperzinyl)carbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-1Hpyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 272

Chlorosulfonyl isocyanate, 4,4-dioxo-4-thiomorpholine and then Example258 are reacted according to the procedure for Example 7 to afford1-(3-t-butyl-1-[[3-[[(1-(4,4-dioxo-4-thiomorpholinyl)carbonyl)amino]sulphonyl]-((methylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example GGG

Commercially available 3-nitrobenzamide is reduced with LAH understandard conditions to afford (3-nitrophenyl)methanamine, which isreacted with 4-methoxybenzylisocyanate to afford1-(3-nitrobenzyl)-3-(4-methoxybenzyl)urea. This material is subsequentlyreacted with oxalyl chloride to afford1-(3-nitrobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4,5-trione whosenitro group is reduced and oxidized to afford1-(3-hydrazinylbenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4,5-trione.This material is deprotected with TFA under standard conditions toafford the title compound1-(3-hydrazinylbenzyl)imidazolidine-2,4,5-trione.

Example 273

Utilizing the same synthetic procedure as for Example 164, Example GGG(10 nmol) and Example PP (10.5 mmol) are combined to afford1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea

Example 274

Utilizing the same synthetic procedure as for Example 164, Example GGG(10 mmol) and Example QQ (10.5 mmol) are combined to afford1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.

Example HHH

Commercially available 3-nitrobenzamide is reduced with LAH understandard conditions to afford (3-nitrophenyl)methanamine, which isreacted with N-4-methoxybenzylsulfamic acid and EDC to afford1-(4-methoxybenzyl)-3-benzylsulfonylurea. This material is reacted withoxalyl chloride to afford1-(3-nitrobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,2-dioxo-2-thio-4,5-trionewhose nitro group is reduced and oxidized to afford1-(3-hydrazinylbenzyl)-3-(4-methoxybenzyl)imidazolidine-2,2-dioxo-2-thio-4,5-trione.This material is deprotected with TFA under standard conditions toafford the title compoundI-(3-hydrazinylbenzyl)imidazolidine-2,2-dioxo-2-thio-4,5-trione.

Example 275

Utilizing the same synthetic procedure as for Example 164, Example HHH(10 mmol) and Example PP (10.5 mmol) are combined to afford1-(3-t-butyl-1-(3-((2,2-dioxo-2-thio-4,5-diioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 276

Utilizing the same synthetic procedure as for Example 164, Example HHH(10 mmol) and Example QQ (10.5 mmol) are combined to afford1-(3-t-butyl-1-(3-((2,2-dioxo-2-thio-4,5-diioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.

Example 277

Example CC, 4-methoxy-1-aminonaphthalene and Example E are reacted usingthe procedure for Example 162 to afford1-(5-t-butyl-2-{3-[1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-methoxynaphth-1-yl)-urea.

Example III

A solution of 1-(chloromethyl)-3-nitrobenzene and Example DD arecombined using the procedure for Example 77 to yield2-(4-methoxybenzyl)-5-(3-nitrophenylmethyl)-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-3-one.This material is reduced under standard condition to yield2-(4-methoxybenzyl)-5-(3-aminophenylmethyl)-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-3-one,which was nitrosated and acidified to yield5-(3-hydrazinophenylmethyl)-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-3-one.

Example JJJ

Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH₂Cl₂(25 mL) and cooled in an ice bath. The suspension is stirred for 5 minand 2-naphthoic acid chloride is added dropwise over 5 min. The reactionmixture is stirred an additional 5 min at 0° C., and the reaction iswarmed and stirred at RT for 1 h. The reaction is pour into ethylacetate (100 mL) and water (100 ml). After shaking, the aqueous layer isremoved, the organic layer washed with water, dried (MgSO₄) andconcentrated to afford(Z)-N-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)-2-naphthamide.

Example KKK

Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH₂Cl₂(25 mL) and cooled in an ice bath. The suspension is stirred for 5 minand 1-naphthoic acid chloride is added dropwise over 5 min. The reactionmixture is stirred an additional 5 min at 0° C., and the reaction iswarmed and stirred at RT for 1 h. The reaction is pour into ethylacetate (100 mL) and water (100 ml). After shaking, the aqueous layer isremoved, the organic layer washed with water, dried (MgSO₄) andconcentrated to afford(Z)-N-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)-1-naphthamide

Example LLL

Intermediate HH (5 g, 0.0241 mol) is added to pyridine (5 mL) in CH₂Cl₂(25 mL) and cooled in an ice bath. The suspension is stirred for 5 minand isoquinoloic acid chloride is added dropwise over 5 min. Thereaction mixture is stirred an additional 5 min at 0° C., and thereaction is warmed and stirred at RT for 1 h. The reaction is pour intoethyl acetate (100 mL) and water (100 ml). After shaking, the aqueouslayer is removed, the organic layer washed with water, dried (MgSO₄) andconcentrated to afford(Z)-N-(1-ethoxy-4,4-dimethyl-3-oxopentylidene)isoquinoline-3-carboxamide.

Example 278

Utilizing the same synthetic procedure as for Example 164, Example III(10 mmol) and Example II (10.5 mmol) are combined to afford 1-naphtyl1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)carbamate.

Example 279

Utilizing the same synthetic procedure as for Example 164, Example III(10 mmol) and Example JJJ (10.5 mmol) are combined to afford1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-2-naphthamide.

Example 280

Utilizing the same synthetic procedure as for Example 164 Example III(10 mmol) and Example KKK (10.5 mmol) are combined to afford1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-1-naphthamide.

Example 281

Utilizing the same synthetic procedure as for Example 149, Example III(10 mmol) and Example KKK (10.5 mmol) are combined to afford1-(3-t-butyl-1-(3-((2,4,5-trioxoimidazolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)isoquinoline-3-carboxamide.

Example MMM

Commercially available 3-nitrobenzamide is reduced with LAH understandard conditions to afford (3-nitrophenyl)methanamine, which isreacted with succinic anhydride under standard conditions to afford1-(3-nitrobenzyl)pyrrolidine-2,5-dione. This material is reduced at thenitro group and oxidized to afford1-(3-hydrazinobenzyl)pyrrolidine-2,5-dione.

Example 282

Utilizing the same synthetic procedure as for Example 164, Example MMM(10 mmol) and Example PP (10.5 mmol) are combined to afford1-(3-t-butyl-1-(3-((2,5-dioxopyrrolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.

Example 283

Utilizing the same synthetic procedure as for Example 164, Example MMM(10 mmol) and Example QQ (10.5 mmol) are combined to afford1-(3-t-butyl-1-(3-((2,5-dioxopyrrolidin-1-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.

Example 284

Example C was reacted with LiOH utilizing the procedure for Example 146to yield3-(3-t-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)benzoic acidin 90% overall yield. ¹H NMR (DMSO-d₆): 9.00 (s, 1H), 8.83 (s, 1H),8.25-7.42 (m, 11H), 6.42 (s, 1H), 1.26 (s, 9H); MS (ESI): Expected:412.88 Found: 413.00.

Example 285

Example B was reacted with LiOH utilizing the procedure for Example 146to yield3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)benzoic acidin 90% overall yield. ¹H NMR (DMSO-d₆): δ 9.11 (s, 1H), 8.47 (§, 1H),8.06 (m, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.65 (dd,J=8.0, 7.6 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 6.34(s, 1H), 1.27 (s, 9H); MS (ESI) Expected: 428.49 Found: 429.2 (M+1).

Example NNN

To the solution of phenyl-urea (13.0 g, 95.48 mol) in THF (100 mL) wasslowly added chlorocarbonyl sulfenylchloride (13 mL, 148.85 mmol) at RT.The reaction mixture was refluxed overnight, the volatiles removed invacuo yielded 2-phenyl-1,2,4-thiadiazolidine-3,5-dione as a white solid(4.0 g, 20%). ¹H NMR (DMSO-d₆): δ 12.49 (s, 1H), 7.51 (d, J=8.0 Hz, 2H),7.43 (t, J=7.6 Hz, 2H), 7.27 (t, J=7.2 Hz, 1H).

Example 286

Example E and Example NNN were reacted together utilizing the samegeneral approach as for Example 160 to afford1-(3-t-butyl-1-(3-((3,5-dioxo-2-phenyl-1,2,4-thiadiazolidin-4-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea.¹H NMR (DMSO-d₆): δ8.96 (s, 1H), 8.01-7.21 (m, 16H), 6.40 (s, 1H), 4.85(s, 2H), 1.28 (s, 9 H); MS (ESI): Expected: δ90.21, Found 591.26 (M+1).

Example 287

Example CC, 1-naphthylisocyanate and Example DD were combined utilizingthe same general approach for Example 162 to yield1-(5-t-butyl-2-{3-[5-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-1-naphthylurea.¹H NMR (DMSO-d₆): δ 9.0 (s, 1H), 8.81 (s, 1H), 7.99-7.42 (m, 11H), 6.41(s, 1H), 4.33 (s, 2H), 1.27 (s, 9H); MS (ESI) Exact Mass: 532.19 Found:=533.24

Example 288

Example CC, p-chlorophenylisocyanate and Example DD were combinedutilizing the same general approach for Example 162 to yield1-(5-t-butyl-2-{3-[5-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-(4-chloro-phenyl)-urea.¹H NMR (DMSO-d₆): δ 9.07 (s, 1H), 8.42 (s, 1H), 7.52-7.272 (m, 8H), 6.36(s, 1H), 4.60 (s, 2H), 1.26 (s, 9H); MS (ESI) Exact Mass: 516.13 Found:=517.1

Example 289

Example G and Example NNN were reacted together utilizing the samegeneral approach as for Example 160 to afford1-(3-t-butyl-1-(3-((3,5-dioxo-2-phenyl-1,2,4-thiadiazolidin-4-yl)methyl)phenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea.¹H NMR (DMSO-d₆): δ9.02 (s, 1H), 8.51 (s, 1H), 7.52-7.24 (m, 13H), 6.36(s, 1H), 4.90 (s, 2H), 1.27 (s, 9H); MS (ESI): Expected: 574.16 Found:575.26 (M+1)

Example 290

Example Z and 2,6-dichlorophenylisocyanate were reacted utilizing thesame conditions as for Example 145 to yield ethyl3-(3-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate.¹H NMR (DMSO-d₆): δ 7.46-7.26 (m, 7H), 6.35 (s, 1H), 4.11 (q, J=7.2 Hz,2H), 3.31 (t, J=5.2 Hz, 2H), 2.68 (t, J=5.6 Hz, 2H), 1.32 (s, 9H), 1.24(t, J=7.2 Hz, 3H); MS (ESI): Expected: 502.15 Found: =503.1 (M+1).

Example 291

Example 290 was reacted utilizing the same condition as for Example 146to yield3-(3-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoicacid in >90% yield. ¹H NMR (DMSO-d₆): δ 8.70 (s, 1H), 8.60 (s, 1H)7.50-7.24 (m, 7H), 6.26 (s, 1H), 2.87 (t, J=5.2 Hz, 2H), 2.57 (t, J=5.6Hz, 2H), 1.25 (s, 9H); MS (ESI): Expected: 474.12 Found: 475.18 (M+1).

Example OOO

A mixture of ethyl 3-(4-aminophenyl)acrylate (1.5 g) and 10% Pd onactivated carbon (0.3 g) in ethanol (20 ml) was hydrogenated at 30 psifor 18 h and filtered over Celite. Removal of the volatiles in vacuoprovided ethyl 3-(4-aminophenyl)propionate (1.5 g).

A solution of the crude material from the previous reaction (1.5 g, 8.4mmol) was dissolved in 6 N HCl (9 ml), cooled to 0° C., and vigorouslystirred. Sodium nitrite (0.58 g) in water (7 ml) was added. After 1 h,tin (II) chloride dihydrate (5 g) in 6 N HCl (10 ml) was added. Thereaction mixture was stirred at 0° C. for 3 h. The pH was adjusted to pH7 to yield ethyl3-(4-(3-t-butyl-5-amino-1H-pyrazol-1-yl)phenyl)propanoate.

Example 292

Example OOO and 2,6-dichlorophenylisocyanate were reacted utilizing thesame conditions as for Example 145 to yield ethyl3-(4-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate.¹H NMR (DMSO-d₆): δ 7.45-7.24 (m, 7H), 6.36 (s, 1H), 4.10 (q, J=7.2 Hz,2H), 3.02 (t, J=5.2 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 1.33 (s, 9H), 1.22(t, J=7.2 Hz, 3H); MS (ESI): Expected: 502.15 Found: =503.1 (M+1).

Example 293

Example 292 was reacted utilizing the same condition as for Example 146to yield3-(3-(3-t-butyl-5-(3-(2,6-dichlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoicacid in >90% yield. ¹H NMR (DMSO-d₆): δ 8.66 (s, 1H), 8.58 (s, 1H)7.50-7.28 (m, 7H), 6.27 (s, 1H), 2.85 (t, J=5.2 Hz, 2H), 2.48 (t, J=5.6Hz, 2H), 1.24 (s, 9H); MS (ESI): Expected: 474.12 Found: 475.18 (M+1).

Example 294

Example OOO and p-chlorophenylisocyanate were reacted utilizing the sameconditions as for Example 145 to yield ethyl3-(4-(3-tert-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate.¹H NMR (DMSO-d₆): δ 7.34-7.19 (m, 9H), 6.36 (s, 1H), 4.10 (q, J=7.2 Hz,2H), 2.92 (t, J=5.2 Hz, 2H), 2.58 (t, J=5.6 Hz, 2H), 1.32 (s, 9H), 1.25(t, J=7.2 Hz, 3H); MS (ESI): Exact Mass: 468.19 Found: =469.21 (M+1).

Example 295

Example Z and p-chlorophenylisocyanate were reacted utilizing the sameconditions as for Example 145 to yield ethyl3-(3-(3-tert-butyl-5-(3-(4-chlorophenyl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate.¹H NMR (DMSO-d₆): δ 9.12 (s, 1H), 8.37 (s, 1H), 7.41-7.27 (m, 8H), 6.34(s, 1H), 5.73 (s, 1H), 4.01 (q, J=7.2 Hz, 2H), 2.90 (t, J=5.2 Hz, 2H),2.62 (t, J=5.6 Hz, 2H), 1.25 (s, 9H), 1.125 (t, J=7.2 Hz, 3H); MS (ESI):Exact Mass: 468.19 Found: =469.21 (M+1).

Example 296

Example OOO and 1-naphthylisocyanate were reacted utilizing the sameconditions as for Example 145 to yield ethyl3-(4-(3-tert-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate.δ 7.88-9.95 (m, 13H), 6.27 (s, 1H), 4.04 (q, J=7.2 Hz, 2H), 2.75 (t,J=5.2 Hz, 2H), 2.42 (t, J=5.6 Hz, 2H), 1.27 (s, 9H), 1.20 (t, J=7.2 Hz,3H); MS (ESI): Exact Mass: 484.25 Found: =485.26 (M+1).

Example 297

Example Z and 1-naphthylisocyanate were reacted utilizing the sameconditions as for Example 145 to yield ethyl3-(3-(3-tert-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)phenyl)propanoate.¹H NMR (DMSO-d₆): δ 9.01 (s, 1H), 8.80 (s, 1H), 8.0-7.27 (m, 11H), 6.41(s, 1H), 4.01 (q, J=7.2 Hz, 2H), 2.95 (t, J=5.2 Hz, 2H), 2.72 (t, J=5.6Hz, 2H), 1.27 (s, 9H), 1.15 (t, J=7.2 Hz, 3H); MS (ESI): Exact Mass:484.25 Found: =485.26 (M+1).

Example 298

Example CC, 1-(4-methoxynaphthyl)isocyanate and Example DD were combinedutilizing the same general approach for Example 162 to yield1-(5-t-butyl-2-{3-[5-1,1,4-trioxo-1λ⁶-[1,2,5]thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-1-(4-methoxynaphthyl)urea.¹H NMR (DMSO-d₆): δ 8.69 (s, 1H), 8.61 (s, 1H), 8.15-6.90 (m, 10H), 6.36(s, 1H), 4.37 (s, 2H), 3.93 (s, 3H), 1.22 (s, 9H); MS (ESI) Exact Mass:562.20 Found: =563.2.

Example PPP

In a 250 mL Erlenmeyer flask with a magnetic stir bar,3-phenoxyphenylamine (4.81 g, 0.026 mol) was added to 6 N HCl (40 mL)and cooled with an ice bath to 0° C. A solution of NaNO₂ (2.11 g, 0.0306mol, 1.18 eq.) in water (5 mL) was added drop wise. After 30 min,SnCl₂2H₂O (52.0 g, 0.23 mol, 8.86 eq.) in 6 N HCl (100 mL) was added andthe reaction mixture was allowed to stir for 3 h, and then subsequentlytransferred to a 500 mL round bottom flask. To this,4,4-dimethyl-3-oxopentanenitrile (3.25 g, 0.026 mol) and EtOH (100 ml)were added and the mixture refluxed for 4 h, concentrated in vacuo andthe residue extracted with EtOAc (2×100 mL) and purified by columnchromatography using hexane/EtOAc/Et₃N (8:2:0.2) to yield3-tert-butyl-1-(3-phenoxyphenyl)-1H-pyrazol-5-amine (1.40 g, 17%). mp:108-110° C.; ¹H NMR (CDCl₃): δ 7.3 (m, 10H), 5.7 (s, 1H), 4.9 (brs, 2H),1.3 (s, 9H).

Example 299

In a dry vial with a magnetic stir bar, Example PPP (0.184 g; 0.60 mmol)was dissolved in 2 mL CH₂Cl₂ (anhydrous) followed by the addition ofphenylisocyanate (0.0653 mL; 0.60 mmol; 1 eq.). The reaction was keptunder Ar and stirred for 18 h. Evaporation of solvent gave a crystallinemass that was recrystallized from EtOAc/hexane and then filtered washingwith hexane/EtOAc (4:1) to yield1-[3-tert-butyl-1-(3-phenoxyphenyl)-1H-pyrazol-5-yl]-3-phenylurea (0.150g, 50%). HPLC purity: 96%; ¹H NMR (CDCl₃): δ 7.5 (m, 16H), 6.8 (s, 1H),6.5 (s, 1H), 1.4 (s, 9H).

Example QQQ

To a stirred solution of Example L (1.2 g, 3.5 mmol) in THF (6 ml) wasadded borane-methylsulfide (9 mmol). The mixture was heated to refluxfor 90 min and cooled to RT, and 6 N HCl was added and heated to refluxfor 10 min. The mixture was basified by adding sodium hydroxide,followed by extraction with ethyl acetate. The organic layer was dried(Na₂SO₄) filtered and concentrated in vacuo to yield3-tert-butyl-1-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-amine (0.78g), which was used without further purification.

Example 300

A mixture of Example QQQ (0.35 g, 1.07 mmol) and 1-naphthylisocyanate(0.18 g, 1.05 mmol) in dry CH₂Cl₂ (4 ml) was stirred at RT under N₂ for18 h. The solvent was removed in vacuo and the crude product waspurified by column chromatography using 5% methanol in CH₂Cl₂ (with asmall amount of TEA) as the eluent (0.18 g, off-white solid) to yield1-{3-tert-butyl-1-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-yl}-3-naphthalen-1-yl)urea.mp: 88-90° C.; ¹H NMR (200 MHz, DMSO-d₆): δ 9.07 (s, 1H), 8.80 (s, 1H),8.06-7.92 (m, 3H), 7.69-7.44 (m, 7H), 7.40-7.29 (m, 1H), 6.44 (s, 1H),3.57-3.55 (m, 4H), 3.33-3.11 (m, 4H), 2.40-2.38 (m, 4H), 1.32 (s, 9H);MS

Example 301

The title compound was synthesized in a manner analogous to Example 23utilizing Example QQQ (0.35 g, 1.07 mmol) and 4-chlorophenylisocyanate(0.165 g, 1.05 mmol) to yield1-{3-tert-butyl-1-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea.mp: 82-84° C.; ¹H NMR (200 MHz, DMSO-d₆): δ 9.18 (s, 1H, s), 8.40 (s,1H), 7.53-7.26 (m, 8H), 6.37 (s, 1H), 3.62-3.54 (m, 4H), 2.82-2.78 (m,4H), 2.41-2.39 (m, 4H), 1.30 (s, 9H); MS

All of the references above identified are incorporated by referenceherein. In addition, two simultaneously applications are alsoincorporated by reference, namely Modulation of Protein Functionalities,Ser. No. 10/746,545, filed Dec. 24, 2003, and Anti-Cancer Medicaments,Ser. No. 10/746,607, filed Dec. 24, 2003.

1. An adduct comprising a molecule binding with a kinase, said moleculehaving the formula

wherein: R¹ is selected from the group consisting of aryls andheteroaryls; each X and Y is individually selected from the groupconsisting of —O—, —S—, —NR₆—, —NR₆SO₂—, —NR₆CO—, alkynyls, alkenyls,alkylenes, —O(CH₂)_(h)—, and —NR₆(CH₂)_(h)—, where each h isindividually selected from the group consisting of 1, 2, 3, or 4, andwhere for each of alkylenes, —O(CH₂)_(h)—, and —NR₆(CH₂)_(h)—, one ofthe methylene groups present therein may be optionally double-bonded toa side-chain oxo group except that where —O(CH₂)_(h)— the introductionof the side-chain oxo group does not form an ester moiety; A is selectedfrom the group consisting of aromatic, monocycloheterocyclic, andbicycloheterocyclic rings; D is phenyl or a five- or six-memberedheterocyclic ring selected from the group consisting of pyrazolyl,pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl,thiadiazolyl, thienyl, pyridyl, and pyrimidyl; E is selected from thegroup consisting of phenyl, pyridinyl, and pyrimidinyl; L is selectedfrom the group consisting of —C(O)— and —S(O)₂—; j is 0 or 1; m is 0 or1; n is 0 or 1; p is 0 or 1; q is 0 or 1; t is 0 or 1; Q is selectedfrom the group consisting of

each R₄ group is individually selected from the group consisting of —H,alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, andheterocyclylalkyls except when the R₄ substituent places a heteroatom onan alpha-carbon directly attached to a ring nitrogen on Q; when two R₄groups are bonded with the same atom, the two R₄ groups optionally forman alicyclic or heterocyclic 4-7 membered ring; each R₅ is individuallyselected from the group consisting of —H, alkyls, aryls, heterocyclyls,alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys,alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens,perfluoroalkyls, alkylcarbonyls, and nitros; each R₆ is individuallyselected from the group consisting of —H, alkyls, allyls, andβ-trimethylsilylethyl; each R₈ is individually selected from the groupconsisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;each R₉ group is individually selected from the group consisting of —H,—F, and alkyls, wherein when two R₉ groups are geminal alkyl groups,said geminal alkyl groups may be cyclized to form a 3-6 membered ring; Gis alkylene, N(R₆), O; each Z is individually selected from the groupconsisting of —O— and —N(R₄)—; and each ring of formula (III) optionallyincludes one or more of R₇, where R₇ is a noninterfering substituentindividually selected from the group consisting of —H, alkyls, aryls,heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos,heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios,arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls,alkylsulfonyls, aminosulfonyls, and perfluoroalkyls.
 2. The adduct ofclaim 1, said molecule binding at the region of a switch control pocketof said kinase.
 3. The adduct of claim 2, said switch control pocket ofsaid kinase comprising an amino acid residue sequence operable forbinding to said Formula (III) molecule.
 4. The adduct of claim 2, saidswitch control pocket selected from the group consisting of simple,composite and combined switch control pockets.
 5. The adduct of claim 4,said region being selected from the group consisting of the α-C helix,the α-D helix, the catalytic loop, the switch control ligand sequence,the C-terminal residues, the glycine rich loop residues, andcombinations thereof.
 6. The adduct of claim 5, said α-C helix includingSEQ ID NO.
 2. 7. The adduct of claim 5, said catalytic loop includingSEQ ID NO.
 3. 8. The adduct of claim 5, said switch control ligandsequence being selected from the group consisting of SEQ ID NO. 4, SEQID NO. 5, and combinations thereof.
 9. The adduct of claim 5, saidC-lobe residues selected from SEQ ID NO.
 6. 10. The adduct of claim 5,said glycine rich loop residues taken from SEQ ID NO.
 7. 11. The adductof claim 1, said kinase selected from the group consisting of theconsensus wild type sequence and disease polymorphs thereof.
 12. Theadduct of claim 1, said molecule having the formula

wherein: R¹ is selected from the group consisting of aryls andheteroaryls; each X and Y is individually selected from the groupconsisting of —O—, —S—, —NR₆—, —NR₆SO₂—, —NR₆CO—, alkynyls, alkenyls,alkylenes, —O(CH₂)_(h)—, and —NR₆(CH₂)_(h)—, where each h isindividually selected from the group consisting of 1, 2, 3, or 4, andwhere for each of alkylenes, —O(CH₂)_(h)—, and —NR₆(CH₂)_(h)—, one ofthe methylene groups present therein may be optionally double-bonded toa side-chain oxo group except that where —O(CH₂)_(h)— the introductionof the side-chain oxo group does not form an ester moiety; A is selectedfrom the group consisting of aromatic, monocycloheterocyclic, andbicycloheterocyclic rings; D is phenyl or a five- or six-memberedheterocyclic ring selected from the group consisting of pyrazolyl,pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl,thiadiazolyl, thienyl, pyridyl, and pyrimidyl; E is selected from thegroup consisting of phenyl, pyridinyl, and pyrimidinyl; L is selectedfrom the group consisting of —C(O)— and —S(O)₂—; j is 0 or 1; m is 0 or1; n is 0 or 1; p is 0 or 1; q is 0 or 1; t is 0 or 1; Q is selectedfrom the group consisting of

each R₄ group is individually selected from the group consisting of —H,alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, andheterocyclylalkyls except when the R₄ substituent places a heteroatom onan alpha-carbon directly attached to a ring nitrogen on Q; when two R₄groups are bonded with the same atom, the two R₄ groups optionally forman alicyclic or heterocyclic 4-7 membered ring; each R₅ is individuallyselected from the group consisting of —H, alkyls, aryls, heterocyclyls,alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys,alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens,perfluoroalkyls, alkylcarbonyls, and nitros; each R₆ is individuallyselected from the group consisting of —H, alkyls, allyls, andβ-trimethylsilylethyl; each R₈ is individually selected from the groupconsisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;each R₉ group is individually selected from the group consisting of —H,—F, and alkyls, wherein when two R₉ groups are geminal alkyl groups,said geminal alkyl groups may be cyclized to form a 3-6 membered ring;and G is alkylene, N(R₆), O; each Z is individually selected from thegroup consisting of —O— and —N(R₄)—; each ring of formula (IA)optionally includes one or more of R₇, where R₇ is a noninterferingsubstituent individually selected from the group consisting of —H,alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos,heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios,arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls,alkylsulfonyls, aminosulfonyls, and perfluoroalkyls; except that: when Qis Q-3 or Q-4, then the compound of formula (IA) is not

when Q is Q-7, q is 0, and R₅ and D are phenyl, then A is not phenyl,oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl; when Q is Q-7,R₅ is —OH, Y is —O—, —S—, or —CO—, m is 0, n is 0, p is 0, and A isphenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, orphenyl; when Q is Q-7, R₅ is —OH, m is 0, n is 0, p is 0, t is 0, and Ais phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, orphenyl; when Q is Q-7, then the compound of formula (IA) is not

when Q is Q-8, then Y is not —CH₂O—; when Q is Q-8, the compound offormula (IA) is not

when Q is Q-9, then the compound of formula (IA) is not

when Q is Q-10, t is 0, and E is phenyl, then any R₇ on E is not ano-alkoxy; when Q is Q-10, then the compound of formula (IA) is not

when Q is Q-11, t is 0, and E is phenyl, then any R₇ on E is not ano-alkoxy; when Q is Q-11, then the compound of formula (IA) is not

when Q is Q-15, then the compound of formula (IA) is not

when Q is Q-16 and Y is —NH—, then

 of formula (IA) is not biphenyl; when Q is Q-16 and Y is —S—, then

 of formula (IA) is not phenylsulfonylaminophenyl orphenylcarbonylaminophenyl; when Q is Q-16 and Y is —SO₂NH—, then thecompound of formula (IA) is not

when Q is Q-16 and Y is —CONH—, then

 of formula (IA) is not imidazophenyl; when Q is Q-16 and Y is —CONH—,then the compound of formula (IA) is not

when Q is Q-16 and t is 0, then

 of formula (IA) is not phenylcarbonylphenyl, pyrimidophenyl,phenylpyrimidyl, pyrimidyl, or N-pyrolyl; when Q is Q-17, then thecompound of formula (IA) is not

when Q is Q-21, then the compound of formula (IA) is not

when Q is Q-22, then the compound of formula (IA) is selected from thegroup consisting of

when Q is Q-22 and q is 0, then the compound of formula (IA) is selectedfrom the group consisting of

when Q is Q-23, then the compound of formula (IA) is not

when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of formula (IA)is selected from the group consisting of

wherein each W is individually selected from the group consisting of—CH— and —N—; each G₁ is individually selected from the group consistingof —O—, —S—, and —N(R₄)—; and * denotes the point of attachment to Q-24,Q-25, Q-26, or Q-31 as follows:

wherein each Z is individually selected from the group consisting of —O—and —N(R₄)—; when Q is Q-31, then the compound of formula (IA) is not

when Q is Q-28 or Q-29 and t is 0, then the compound of formula (IA) isnot

when Q is Q-28 or Q-29 and Y is an ether linkage, then the compound offormula (IA) is not

when Q is Q-28 or Q-29 and Y is —CONH—, then the compound of formula(IA) is not

when Q is Q-32, then

 is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl; when Qis Q-32, Y is —CONH—, q is 0, m is 0, and

 of formula (IA) is —CONH—, then A is not phenyl; when Q is Q-32, q is0, m is 0, and

 is —CONH—, then the compound of formula (IA) is not

when Q is Q-32, D is thiazolyl, q is 0, t is 0, p is 0, n is 0, and m is0, then A is not phenyl or 2-pyridone; when Q is Q-32, D is oxazolyl orisoxazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is notphenyl; when Q is Q-32, D is pyrimidyl q is 0, t is 0, p is 0, n is 0,and m is 0, then A is not phenyl; when Q is Q-32 and Y is an etherlinkage, then

 of formula (IA) is not biphenyl or phenyloxazolyl; when Q is Q-32 and Yis —CH═CH—, then

 of formula (IA) is not phenylaminophenyl; when Q is Q-32, then thecompound of formula (IA) is not

when Q is Q-35 as shown

wherein G is selected from the group consisting of —O—, —S—, —NR₄—, and—CH₂—, k is 0 or 1, and u is 1, 2, 3, or 4, then

 is selected from the group consisting of

except that the compound of formula (IA) is not


13. An adduct comprising a molecule binding with a p 38-alpha kinase,said molecule having the formulaA-T-(L)_(n)-(NH)_(p)-D-(E)_(q)-(Y)_(t)-Q  (IB) wherein: Y is selectedfrom the group consisting of —O—, —S—, —NR₆—, —NR₆SO₂—, —NR₆CO—,alkynyls, alkenyls, alkylenes, —O(CH₂)_(h)—, and —NR₆(CH₂)_(h)—, whereeach h is individually selected from the group consisting of 1, 2, 3, or4, and where for each of alkylenes, —O(CH₂)_(h)—, and —NR₆(CH₂)_(h)—,one of the methylene groups present therein may be optionallydouble-bonded to a side-chain oxo group except that where —O(CH₂)_(h)—the introduction of the side-chain oxo group does not form an estermoiety; A is selected from the group consisting of aromatic,monocycloheterocyclic, and bicycloheterocyclic rings; and mostpreferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl,pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl,benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl,benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and

where each W1 is individually selected form the group consisting of —CH—and —N—. D is phenyl or a five- or six-membered heterocyclic ringselected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl,oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl,and pyrimidyl; E is selected from the group consisting of phenyl,pyridinyl, and pyrimidinyl; L is selected from the group consisting of—C(O)— and —S(O)₂—; T is N₆, O, alkylene, —O(CH₂)_(h)—, or—NR₆(CH₂)_(h)—, where each h is individually selected from the groupconsisting of 1, 2, 3, or 4, or T is absent wherein A is directly bondedto -(L)_(n)(NH)_(p)-D-(E)_(q)-(Y)_(t)-Q; n is 0 or 1; p is 0 or 1; q is0 or 1; t is 0 or 1; v is 1, 2, or 3; x is 1 or 2; Q is selected fromthe group consisting of formulae Q36-Q59, inclusive, said Q36-Q59 groupsbeing selected from the group consisting of

each R₄ group is individually selected from the group consisting of —H,alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, andheterocyclylalkyls except when the R₄ substituent places a heteroatom onan alpha-carbon directly attached to a ring nitrogen on Q; when two R₄groups are bonded with the same atom, the two R₄ groups optionally forman alicyclic or heterocyclic 4-7 membered ring; each R₆ is individuallyselected from the group consisting of —H, alkyls, allyls, andB-trimethylsilylethyl; each R₈ is individually selected from the groupconsisting of alkyls, phenyl, naphthyl, aralkyls, heterocyclyls, andheterocyclylalkyls; each R₉ group is individually selected from thegroup consisting of —H, —F, and alkyls, wherein when two R₉ groups aregeminal alkyl groups, said geminal alkyl groups may be cyclized to forma 3-6 membered ring; each R⁹, group is individually selected from thegroup consisting of —F, and alkyls, wherein when two R₉, groups aregeminal alkyl groups, said geminal alkyl groups may be cyclized to forma 3-6 membered ring; each R₁₀ is alkyl or perfluoroalkyl; G is alkylene,N(R₆), O; and each Z is individually selected from the group consistingof —O— and —N(R₄)—; and each ring of formula (IB) optionally includesone or more of R_(7′), where R_(7′) is a substituent individuallyselected from the group consisting of —H, alkyls, aryls, heterocyclyls,alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys,alkoxys, perfluoroalkoxys, aryloxys, alkylthios, arthylthios, cyanos,halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls,aminosulfonyls, perfluoroalkyls; aminooxaloylamino;alkylaminooxaloylamino; dialkylaminooxaloylamino;morpholinooxaloylamino; piperazinooxaloylamino; alkoxycarbonylamino;heterocyclyloxycarbonylamino; heterocyclylalkyloxycarbonylamino;heterocyclylcarbonylamino; heterocyclylalkylcarbonylamino;aminoalkyloxycarbonylamino; alkylaminoalkyloxycarbonylamino; ordialkylaminoalkyloxycarbonylamino,
 14. The adduct of claim 13, saidmolecule binding at the region of a switch control pocket of saidkinase.
 15. The adduct of claim 14, said switch control pocket of saidkinase comprising an amino acid residue sequence operable for binding tosaid molecule.
 16. The adduct of claim 14, said switch control pocketselected from the group consisting of simple, composite and combinedswitch control pockets.
 17. The adduct of claim 14, said region beingselected from the group consisting of the α-C helix, the α-D helix, thecatalytic loop, the switch control ligand sequence, the C-terminalresidues, the glycine rich loop residues, and combinations thereof. 18.The adduct of claim 17, said α-C helix including SEQ ID NO.
 2. 19. Theadduct of claim 17, said catalytic loop including SEQ ID NO.
 3. 20. Theadduct of claim 17, said switch control sequence being selected from thegroup consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinationsthereof.
 21. The adduct of claim 17, said C-lobe residues selected fromthe group consisting of SEQ ID NO.
 6. 22. The adduct of claim 17, saidglycine rich loop residues including SEQ ID NO.
 7. 23. The adduct ofclaim 13, said kinase selected from the group consisting of theconsensus wild type P 38-alpha kinase sequence and disease polymorphsthereof.
 24. A kinase-modulator adduct comprising a p38-alpha kinasehaving a switch control pocket with a non-naturally occurring moleculebound to the kinase at the region of said switch control pocket, saidmolecule serving to at least partially regulate the biological activityof said protein by inducing or restricting the conformation of theprotein.
 25. The adduct of claim 24, said molecule serving to induce aconformation change in said kinase.
 26. The adduct of claim 24, saidmolecule serving to restrict a conformation change in said kinase. 27.The adduct of claim 24, said region of the switch control pocket beingselected from the group consisting of the α-C helix, the α-D helix, thecatalytic loop, the switch control ligand sequence, the C-terminalresidues, the glycine rich loop residues, and combinations thereof. 28.The adduct of claim 27, said α-C helix including SEQ ID NO.
 2. 29. Theadduct of claim 27, said catalytic loop including SEQ ID NO.
 3. 30. Theadduct of claim 27, said switch control sequence being selected from thegroup consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinationsthereof.
 31. The adduct of claim 27, said C-lobe residues selected fromthe group consisting of SEQ ID NO.
 6. 32. The adduct of claim 27, saidglycine rich loop residues including SEQ ID NO.
 7. 33. The adduct ofclaim 24, said kinase also having a switch control ligand, said ligandinteracting in vivo with said pocket to regulate the conformation andbiological activity of said kinase such that the kinase will assume afirst conformation and a first biological activity upon saidligand-pocket interaction, and will assume a second, differentconformation and biological activity in the absence of saidligand-pocket interaction.
 34. The adduct of claim 24, said pocket beingan on-pocket, said molecule binding with said kinase at the region ofsaid on-pocket as an agonist.
 35. The adduct of claim 24, said pocketbeing an on-pocket, said molecule binding with said kinase at the regionof said on-pocket as an antagonist.
 36. The adduct of claim 24, saidpocket being an off-pocket, said molecule binding with said kinase atthe region of said off-pocket as an agonist.